3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives

ABSTRACT

The invention relates to 3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

This application is a continuation of U.S. Non-Provisional patentapplication Ser. No. 15/979,932, filed May 15, 2018, which is acontinuation of U.S. Non-Provisional patent application Ser. No.15/405,482 filed Jan. 13, 2017, which claims foreign priority ofEuropean Patent Application No. 16 151 011.0, filed Jan. 13, 2016, thedisclosures of which are incorporated herein by reference.

The invention relates to3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives,their preparation and use in medicine, particularly in variousneurological disorders, including but not limited to pain,neurodegenerative disorders, neuroinflammatory disorders,neuropsychiatric disorders, substance abuse/dependence.

Opioid receptors are a group of Gi/o protein-coupled receptors which arewidely distributed in the human body. The opioid receptors are currentlysubdivided into four major classes, i.e. the three classical opioidreceptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, anddelta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1)receptor, which was more recently discovered based on its high homologywith said classical opioid receptors. After identification of theendogenous ligand of the ORL-1 receptor, known as nociceptin/orphaninFQ, a highly basic 17 amino acid peptide isolated from tissue extractsin 1995, the ORL-1 receptor was renamed “nociceptin opioid peptidereceptor” and abbreviated as “NOP-receptor”.

The classical opioid receptors (MOP, KOP and DOP) as well as the NOPreceptor are widely distributed/expressed in the human body, includingin the brain, the spinal cord, on peripheral sensory neurons and theintestinal tract, wherein the distribution pattern differs between thedifferent receptor classes.

Nociceptin acts at the molecular and cellular level in very much thesame way as opioids. However, its pharmacological effects sometimesdiffer from, and even oppose those of opioids. NOP-receptor activationtranslates into a complex pharmacology of pain modulation, which,depending on route of administration, pain model and species involved,leads to either pronociceptive or antinociceptive activity. Furthermore,the NOP receptor system is upregulated under conditions of chronic pain.Systemic administration of selective NOP receptor agonists was found toexert a potent and efficacious analgesia in non-human primate models ofacute and inflammatory pain in the absence of side effects. Theactivation of NOP receptors has been demonstrated to be devoid ofreinforcing effects but to inhibit opioid-mediated reward in rodents andnon-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171(16): 3777-3800, and references therein).

Besides the involvement of the NOP receptor in nociception, results frompreclinical experiments suggest that NOP receptor agonists might beuseful inter alia in the treatment of neuropsychiatric disorders (Witkinet al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al.,Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOPreceptor is also implicated to modulate not only pain but alsoneuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).

Strong opioids acting at the MOP receptor site are widely used to treatmoderate to severe acute and chronic pain. However, the therapeuticwindow of strong opioids is limited by severe side effects such asnausea and vomiting, constipation, dizziness, somnolence, respiratorydepression, physical dependence and abuse. Furthermore, it is known thatMOP receptor agonists show only reduced effectiveness under conditionsof chronic and neuropathic pain.

It is known that some of the above mentioned side-effects of strongopioids are mediated by activation of classic opioid-receptors withinthe central nervous system. Furthermore, peripheral opioid receptors,when activated, can inhibit transmission of nociceptive signals shown inboth, clinical and animal studies (Gupta et al., 2001; Kalso et al.,2002; Stein et al., 2003; Zollner et al., 2008).

Thus, to avoid CNS-mediated adverse effects after systemicadministration, one approach has been to provide peripherally restrictedopioid receptor ligands that do not easily cross the blood-brain barrierand therefore distribute poorly to the central nervous system (see forinstance WO 2015/192039). Such peripherally acting compounds mightcombine effective analgesia with limited side-effects.

Another approach has been to provide compounds which interact with boththe NOP receptor and the MOP receptor. Such compounds have for instancebeen described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.

A further approach has been to provide multi-opioid receptor analgesicsthat modulate more than one of the opioid receptor subtypes to provideadditive or synergistic analgesia and/or reduced side effects like abuseliability or tolerance.

On the one hand, it would be desirable to provide analgesics thatselectively act on the NOP receptor system but less pronounced on theclassic opioid receptor system, especially MOP receptor system, whereasit would be desirable to distinguish between central nervous activityand peripheral nervous activity. On the other hand, it would bedesirable to provide analgesics that act on the NOP receptor system andalso to a balanced degree on the MOP receptor system, whereas it wouldbe desirable to distinguish between central nervous activity andperipheral nervous activity.

There is a need for medicaments which are effective in the treatment ofpain and which have advantages compared to the compounds of the priorart. Where possible, such medicaments should contain such a small doseof active ingredient that satisfactory pain therapy can be ensuredwithout the occurrence of intolerable treatment-emergent adverse events.

It is an object of the invention to provide pharmacologically activecompounds, preferably analgesics that have advantages compared to theprior art.

This object has been achieved by the subject-matter of the patentclaims.

A first aspect of the invention relates to3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivativesaccording to general formula (I)

whereinR¹ and R² independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted; ora 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted;orR¹ and R² together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; preferablywith the proviso that R¹ and R² do not simultaneously mean —H;R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;R⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 6-14-memberedaryl moiety is optionally connected through —C(═O)—, —C(═O)O—,—C(═O)O—CH₂—, or —S(═O)₂—; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;X means —O—, —S— or —NR⁶—;R⁵ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;in case X means NR⁶, R⁶ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;or R⁷ and R⁸ together with the carbon atom to which they are attachedform a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted;wherein “mono- or polysubstituted” means that one or more hydrogen atomsare replaced by a substituent independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹,—C(═O)OR²¹, —C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃,═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹, —OC(═O)NR²¹R²², —NO₂, —NR²¹R²²,—NR²¹—(CH₂)₁₋₆—C(═O)R²², —NR²¹—(CH₂)₁₋₆—C(═O)OR²²,—NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²², —NR²¹C(═O)—OR²²,—NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹, —S(═O)₂R²¹,—S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²;whereinR²¹, R²² and R²³ independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, and —O—C₁-C₆-alkyl;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²²,—NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or —S(═O)₂NR²¹R²²together with the nitrogen atom to which they are attached form a ringand mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(B)—(CH₂)₂—,wherein R^(B) means —H or —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br and —I;or a physiologically acceptable salt thereof.

Preferably, aryl includes but is not limited to phenyl and naphthyl.Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole,-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,-imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,-benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl,-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,-benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is notlimited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl.Preferably, heterocycloalkyl includes but is not limited to -aziridinyl,-azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,-sulfamorpholinyl, -oxiridinyl, -oxetanyl, -tetrahydropyranyl, and-pyranyl.

When a moiety is connected through an asymmetric group such as —C(═O)O—or —C(═O)O—CH₂—, said asymmetric group may be arranged in eitherdirection. For example, when R⁴ is connected to the core structurethrough —C(═O)O—, the arrangement may be either R⁴—C(═O)O-core orcore-C(═O)O—R⁴.

In preferred embodiments of the compound according to the invention,

R⁷ and R⁸ independently of one another mean —H or —C₁-C₆-alkyl;preferably —H or —CH₃; or R⁷ and R⁸ together with the carbon atom towhich they are attached form a 3-12-membered cycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably cyclopropyl, cyclobutyl or cyclopentyl, in each caseunsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferablyoxetanly, tetrahydrofuranyl or tetrahydropyranyl, in each caseunsubstituted; and/orR⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl;preferably —H.

In a preferred embodiment of the compound according to the invention, R¹means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹means —H and R² means —CH₃.

In another preferred embodiment of the compound according to theinvention, R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.Preferably, R¹ means —CH₃ and R² means —CH₃.

In still another preferred embodiment of the compound according to theinvention, R¹ and R² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—. Preferably, R¹ and R² togetherwith the nitrogen atom to which they are attached form a ring and mean—(CH₂)₃—.

In yet another preferred embodiment,

—R¹ means —H or —CH₃; and—R² means a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered cycloalkyl moiety is connectedthrough —CH₂—, unsubstituted; preferably —CH₂-cycloalkyl,—CH₂-cyclobutyl or —CH₂-cyclopentyl; or R² means a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted;wherein said 3-12-membered heterocycloalkyl moiety is connected through—CH₂—, unsubstituted; preferably —CH₂-oxetanyl or—CH₂-tetrahydrofuranyl.

In a preferred embodiment of the compound according to the invention, R³means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with —OCH₃.

In another preferred embodiment of the compound according to theinvention, R³ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted, optionally connected through —C₁-C₆-alkylene-, linearor branched, saturated or unsaturated, unsubstituted. In a preferredembodiment, R³ means -phenyl unsubstituted, mono- or polysubstituted.More preferably, R³ means -phenyl unsubstituted, mono- or disubstitutedwith —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃, preferably —F.In another preferred embodiment, R³ means -benzyl unsubstituted, mono-or polysubstituted. More preferably, R³ means -benzyl unsubstituted,mono- or disubstituted with —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or—OCH₂OCH₃, preferably —F.

In still another preferred embodiment of the compound according to theinvention, R³ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted. Preferably, R³ means -thienyl or -pyridinyl,in each case unsubstituted, mono- or polysubstituted. More preferably,R³ means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in eachcase unsubstituted or monosubstituted with —F, —Cl or —CH₃.

In a preferred embodiment of the compound according to the invention, R⁴means —H.

In another preferred embodiment of the compound according to theinvention, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with a substituent selected from thegroup consisting of —F, —Cl, —Br, —I, —CN, —CF₃, —OH, —O—C₁-C₄-alkyl,—OCF₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —OC(═O)C₁-C₄-alkyl,—C(═O)C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)NHC₁—C₄-alkylene-CN,—C(═O)NHC₁—C₄-alkylene-O—C₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂;—S(═O)C₁-C₄-alkyl, and —S(═O)₂C₁-C₄-alkyl; or with —C(═O)NR²¹R²² whereinR²¹ and R²² together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—, —(CH₂)₂—O—(CH₂)₂—, or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl; or with—C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; orwith —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH.More preferably, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or monosubstituted with —O—C₁-C₄-alkyl or—C(═O)N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to theinvention, R⁴ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered cycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂—or —CH₂CH₂—. More preferably, R⁴ means a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁴means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means-oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connectedthrough —CH₂— or —CH₂CH₂—.

In yet another preferred embodiment of the compound according to theinvention, R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 6-14-membered aryl moiety is connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R⁴ means -phenyl,unsubstituted, mono- or polysubstituted; wherein said -phenyl isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -phenyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -phenyl is connected through —CH₂— or —CH₂CH₂—.

In a further preferred embodiment of the compound according to theinvention, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis connected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said -phenyl is connected through —CH₂— or—CH₂CH₂—. More preferably, R⁴ means -pyridinyl, -pyrimidinyl,-pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,—C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl,or -pyrazolinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵means —H.

In another preferred embodiment of the compound according to theinvention, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted, mono-or polysubstituted. More preferably, R⁵ means —C₁-C₆-alkyl, linear orbranched, saturated, unsubstituted or monosubstituted with a substituentselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁₋C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl.

In still another preferred embodiment of the compound according to theinvention, R⁵ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted, wherein said3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; preferably through —CH₂— or—CH₂CH₂—. Preferably, R⁵ means a 3-6-membered cycloalkyl moiety,saturated, unsubstituted, mono- or polysubstituted, wherein said3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated, unsubstituted. More preferably, R⁵ means-cyclobutyl, unsubstituted or monosubstituted with —F, —OH, —CN or—C₁-C₄-alkyl, wherein said -cyclobutyl is connected through —CH₂— or—CH₂CH₂—.

In yet another preferred embodiment of the compound according to theinvention, R⁵ means a 3-12-membered heterocycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R⁵ means a4-6-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted. More preferably, R⁵ means-heterocyclobutyl, unsubstituted.

In a further preferred embodiment of the compound according to theinvention, R⁵ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.Preferably, R⁵ means a 5-6-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted, wherein said 5-6-membered heteroaryl moiety isoptionally connected through —CH₂—. More preferably, R⁵ means a5-6-membered heteroaryl moiety, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl, wherein said 5-6-membered heteroaryl moiety isoptionally connected through —CH₂—. Still more preferably, R⁵ means-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl, whereinsaid -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionallyconnected through —CH₂—.

In a preferred embodiment of the compound according to the invention, Xmeans NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, Xmeans NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 5-6-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted. More preferably, Xmeans NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which theyare attached form -pyrrolidinyl, -pyrimidinyl, -morpholinyl,-thiomorpholinyl, -thiomorpholinyl dioxide, or -piperazinyl, in eachcase unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of ═O, —OH, and —C(═O)NH₂, wherein said -pyrrolidinyl,-pyrimidinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide,or -piperazinyl is optionally condensed with an imidazole moiety,unsubstituted.

In a preferred embodiment of the compound according to the invention, R⁵means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —OH,—S(═O)C₁-C₄-alkyl and —S(═O)₂ C₁-C₄-alkyl;-cyclobutyl, unsubstituted or monosubstituted with —OH; wherein said-cyclobutyl is connected through —CH₂—;-heterocyclobutyl, unsubstituted; or-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—C₁, Br, —I, —OH, —O—C₁-C₄-alkyl, —CN, and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionallyconnected through —CH₂—;in case X means NR⁶, R⁶ means —H or —CH₃;or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a piperidine moiety, a pyrrolidine moiety,a morpholine moiety, a thiomorpholine moiety, a thiomorpholine dioxidemoiety, or a piperazine moiety, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of ═O, —OH, and—C(═O)NH₂; wherein said piperidine moiety, pyrrolidine moiety,morpholine moiety, thiomorpholine moiety, thiomorpholine dioxide moiety,or piperazine moiety is optionally condensed with an imidazole moiety,unsubstituted.

In a preferred embodiment of the compound according to the invention, Xmeans NR⁶ and R⁶ means —H or —C₁-C₆-alkyl, linear or branched, saturatedor unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁶means —H or —CH₃. More preferably, R⁶ means —H.

In preferred embodiments the compound according to the invention has astructure according to any of general formulas (II-A) to (VIII-C):

wherein in each caseR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and X are defined as above,R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; preferably —H or —OH;R^(D) means —H or —F;or a physiologically acceptable salt thereof.

Preferably, the substructure of the compounds according to generalformula (I) represented by —C(═O)—X—R⁵ (R⁵, X, R⁷, R⁸, R⁹ and R¹⁰), i.e.

or the corresponding substructure of any of above general formulas(II-A) to (VIII-C) has preferably a meaning selected from the groupconsisting of:

In particularly preferred embodiments of the compound according to theinvention,

R¹ means —H or —CH₃; and/orR² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;preferably, R² means —CH₃ or —CH₂CH₃; more preferably, R¹ and R² bothmean —CH₃; and/orR³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —CN, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃,—C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, —SOCH₃ and—SO₂CH₃; preferably, R³ means -phenyl, -thienyl or -pyridinyl, in eachcase unsubstituted or substituted with —F; more preferably, R³ meansphenyl, unsubstituted or monosubstituted with —F; and/orR⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, and —O—C₁-C₄-alkyl;3-6-membered cycloalkyl, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl,wherein said 3-6-membered cycloalkyl is connected through—C₁-C₆-alkylene; preferably, R⁴ means 3-6-membered cycloalkyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-memberedcycloalkyl is connected through —CH₂— or —CH₂CH₂—; more preferably, R⁴means -cyclopropyl or -cyclobutyl, unsubstituted or monosubstituted with—OH, wherein said -cyclopropyl or -cyclobutyl is connected through—CH₂—; or3-6-membered heterocycloalkyl, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and—O—C₁-C₄-alkyl, wherein said 3-6-membered heterocycloalkyl is connectedthrough —C₁-C₆-alkylene; and/orX means —O— or —NR⁶—; and/orR⁵ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —OH,—S(═O)C₁-C₄-alkyl and —S(═O)₂ C₁-C₄-alkyl;-cyclobutyl, unsubstituted or monosubstituted with —OH; wherein said-cyclobutyl is connected through —CH₂—;-heterocyclobutyl, unsubstituted; or-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, Br, —I, —OH, —O—C₁-C₄-alkyl, —CN, and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionallyconnected through —CH₂—; preferably pyridinyl or pyridazinyl, in eachcase unsubstituted; and/orin case X means NR⁶, R⁶ means —H or —CH₃, preferably —H;or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a piperidine moiety, a pyrrolidine moiety,a morpholine moiety, a thiomorpholine moiety, a thiomorpholine dioxidemoiety, or a piperazine moiety, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of ═O, —OH, and—C(═O)NH₂; wherein said piperidine moiety, pyrrolidine moiety,morpholine moiety, thiomorpholine moiety, thiomorpholine dioxide moiety,or piperazine moiety is optionally condensed with an imidazole moiety,unsubstituted; and/orR⁷ and R⁸ independently of one another mean —H or —CH₃; orR⁷ and R⁸ together with the carbon atom to which they are attached forma ring selected from the group consisting of cyclopropyl, cyclobutyl,heterocyclobutyl and heterocyclohexyl, in each case unsubstituted;and/orR⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

In particularly preferred embodiments of the compound according to theinvention,

R¹ means —H or —CH₃; and/orR² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;preferably, R² means —CH₃ or —CH₂CH₃; more preferably, R¹ and R² bothmean —CH₃; and/orR³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —CN, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃,—C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ andSO₂CH₃; preferably, R³ means -phenyl, -thienyl or -pyridinyl, in eachcase unsubstituted or substituted with —F; more preferably, R³ meansphenyl, unsubstituted; and/orR⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, and —O—C₁-C₄-alkyl; or3-6-membered cycloalkyl, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl,wherein said 3-6-membered cycloalkyl is connected through—C₁-C₆-alkylene; preferably, R⁴ means 3-6-membered cycloalkyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-memberedcycloalkyl is connected through —CH₂— or —CH₂CH₂—; more preferably, R⁴means -cyclobutyl, unsubstituted or monosubstituted with —OH, whereinsaid -cyclobutyl is connected through —CH₂—; and/orX means —O— or —NR⁶—; and/orR⁵ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —OH,—S(═O)C₁-C₄-alkyl and —S(═O)₂ C₁-C₄-alkyl;-cyclobutyl, unsubstituted or monosubstituted with —OH; wherein said-cyclobutyl is connected through —CH₂—;-heterocyclobutyl, unsubstituted; or-oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, Br, —I, —OH, —O—C₁-C₄-alkyl, —CN, and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionallyconnected through —CH₂—; preferably pyridinyl or pyridazinyl, in eachcase unsubstituted; and/orin case X means NR⁶, R⁶ means —H or —CH₃, preferably R⁶ means —H; and/oror in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a piperidine moiety, a pyrrolidine moiety,a morpholine moiety, a thiomorpholine moiety, a thiomorpholine dioxidemoiety, or a piperazine moiety, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of ═O, —OH, and—C(═O)NH₂; wherein said piperidine moiety, pyrrolidine moiety,morpholine moiety, thiomorpholine moiety, thiomorpholine dioxide moiety,or piperazine moiety is optionally condensed with an imidazole moiety,unsubstituted; and/orR⁷ and R⁸ independently of one another mean —H or —CH₃; and/orR⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

Preferably, the compound according to the invention is selected from thegroup consisting of

SC_5001CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide SC_5002CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5003CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamideSC_5004 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-propionamideSC_5005 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-propionamideSC_5006 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-propionamideSC_5007 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-propionamideSC_5008 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-propionamideSC_5009 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-propionamideSC_5010 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-propionamideSC_5011 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-propionamideSC_5012 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-propionamide SC_5013CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-propionamide SC_5014CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-piperidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5015CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5016CIS-1-(Cyclobutyl-methyl)-3-[3-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5017CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-(3-hydroxy-piperidin-1-yl)-3-oxo-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5018CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-propionamideSC_5019CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-oxo-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_5020CIS-3-[3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-N,N-dimethyl-propionamideSC_5022CIS-N-(2-Cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamideSC_5023CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-2-yl-propionamide SC_5024CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-2-yl)-propionamideSC_5025CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-propionamideSC_5026CIS-3-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5027CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5028CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5029CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5030CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide SC_5031CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5032CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5033CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide SC_5034CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5035CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5036CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-propionamide SC_5037CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-propionamide SC_5038CIS-2-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-2-methyl-propionamide SC_5039CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-propionamideSC_5040 CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5041CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[3-oxo-3-(3-oxo-piperazin-1-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5042CIS-(2R)-1-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoyl]-pyrrolidine-2-carboxylic acidamide SC_5043CIS-N-(Carbamoyl-methyl)-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5044CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-propionamide SC_5045CIS-3-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5046CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5047CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5048CIS-3-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5049CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5051CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide SC_5052CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5053CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-propionamide SC_5054CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5055CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide SC_5056CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5057CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5058CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5059CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide SC_5060CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5064CIS-3-[8-(Ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5066CIS-3-[8-(Ethyl-methyl-amino)-1-methyl-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5067CIS-2,2-Dimethyl-3-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-propionamide SC_5069CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide SC_5070CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide SC_5071CIS-3-[1-(Cyclobutyl-methyl)-8-ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5072CIS-3-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5073CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5074CIS-3-[8-(Ethyl-methyl-amino)-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5076CIS-8-Dimethylamino-3-(2,2-dimethyl-3-morpholin-4-yl-3-oxo-propyl)-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5077CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamideSC_5078CIS-3-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5079CIS-8-Dimethylamino-3-[3-(1,1-dioxo-[1,4]thiazinan-4-yl)-2,2-dimethyl-3-oxo-propyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_5081TRANS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5082TRANS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide SC_5083CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-propionamide SC_5084CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5085CIS-1-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)cyclopropanecarboxamide SC_5086CIS-3-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)oxetane-3-carboxamide SC_5087CIS-3-(1-(cyclopropylmethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide SC_5088CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanamide SC_5089CIS-3-(8-(dimethylamino)-1-((1-fluorocyclopropyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamideand the physiologically acceptable salts thereof.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can belinear or branched, saturated or unsaturated. Linear saturated alkylincludes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.Examples of branched saturated alkyl include but are not limited toiso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturatedalkyl include but are not limited to vinyl, propenyl, allyl, andpropargyl.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can beunsubstituted, mono- or polysubstituted. Examples of substituted alkylinclude but are not limited to —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—CH₂CH₂S(═O)₂CH₃, —CH₂C(═O)NH₂, —C(CH₃)₂C(═O)NH₂, —CH₂C(CH₃)₂C(═O)NH₂,and —CH₂CH₂C(═O)N(CH₃)₂.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of saturatedalkylene include but are not limited to —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH(CH₃)—, —C(CH₃)₂CH₂—,—CH₂C(CH₃)₂—, —CH(CH₃)C(CH₃)₂—, —C(CH₃)₂CH(CH₃)—, C(CH₃)₂C(CH₃)₂—,—CH₂CH₂CH₂—, and —C(CH₃)₂CH₂CH₂—. Examples of unsaturated alkyleneinclude but are not limited to —CH═CH—, —C≡C—, —C(CH₃)═CH—, —CH═C(CH₃)—,—C(CH₃)═C(CH₃)—, —CH₂CH═CH—, —CH═CHCH₂—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of substituted—C₁-C₆-alkylene-include but are not limited to —CHF—, —CF₂—, —CHOH— and—C(═O)—.

According to the invention, moieties may be connected through—C₁-C₆-alkylene-, i.e. the moieties may not be directly bound to thecore structure of compound according to general formula (I), but may beconnected to the core structure of compound according to general formula(I) or its periphery through a —C₁-C₆-alkylene-linker.

According to the invention, “3-12-membered cycloalkyl moiety” means anon-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to12 ring carbon atoms but no heteroatoms in the ring. Examples ofpreferred saturated 3-12-membered cycloalkyl moieties according to theinvention include but are not limited to cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, anddecaline. Examples of preferred unsaturated 3-12-membered cycloalkylmoiety moieties according to the invention include but are not limitedto cyclopropene, cyclobutene, cyclopentene, cyclopentadiene,cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The3-12-membered cycloalkyl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 6-14-memberedaryl moiety, unsubstituted, mono- or polysubstituted; and/or with a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 3-12-membered heterocycloalkyl moieties includebut are not limited to octahydro-1H-indol, decahydroquinoline,decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, anddecahydroquinoxalin, which in each case are connected through the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 6-14-membered aryl moieties include but are notlimited to 2,3-dihydro-1H-indene and tetraline, which in each case areconnected through the 3-12-membered cycloalkyl moiety. Examples of3-12-membered cycloalkyl moieties condensed with 5-14-memberedheteroaryl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 3-12-membered cycloalkyl moiety.

According to the invention, the 3-12-membered cycloalkyl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-memberedcycloalkyl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Examples include but are not limited to—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, and—CH₂CH₂-cyclohexyl.

According to the invention, unless expressly stated otherwise, the3-12-membered cycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered cycloalkylmoieties include but are not limited to —CH₂-1-hydroxy-cyclobutyl.

According to the invention, “3-12-membered heterocycloalkyl moiety”means a non-aromatic, monocyclic, bicyclic or tricyclic moietycomprising 3 to 12 ring atoms, wherein each cycle comprisesindependently of one another 1, 2, 3, 4 or more heteroatomsindependently of one another selected from the group consisting ofnitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or(S(═O)₂), whereas the remaining ring atoms are carbon atoms, and whereasbicyclic or tricyclic systems may share common heteroatom(s). Examplesof preferred saturated 3-12-membered heterocycloalkyl moieties accordingto the invention include but are not limited to aziridin, azetidine,pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine,triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane,tetrahydropyrane, thiirane, thietane, tetrahydrothiophene, diazepane,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,thiadiazolidine, morpholine, thiomorpholine. Examples of preferredunsaturated 3-12-membered heterocycloalkyl moiety moieties according tothe invention include but are not limited to oxazoline, pyrazoline,imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.The 3-12-membered heterocycloalkyl moiety, which is bonded to thecompound according to the invention, in its periphery may optionally becondensed with a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; and/or with a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered heterocycloalkyl moieties. Examples of 3-12-memberedheterocycloalkyl moieties condensed with 3-12-membered cycloalkylmoieties include but are not limited to octahydro-1H-indol,decahydroquinoline, decahydroisoquinoline,octahydro-2H-benzo[b][1,4]oxazin, and decahydroquinoxalin, which in eachcase are connected through the 3-12-membered heterocycloalkyl moiety. Anexamples of a 3-12-membered heterocycloalkyl moiety condensed with a6-14-membered aryl moiety includes but is not limited to1,2,3,4-tetrahydroquinoline, which is connected through the3-12-membered heterocycloalkyl moiety. An example of a 3-12-memberedheterocycloalkyl moiety condensed with a 5-14-membered heteroarylmoieties includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 3-12-membered heterocycloalkyl moiety.

According to the invention, the 3-12-membered heterocycloalkyl moietymay optionally be connected through —C₁-C₆-alkylene-, i.e. the3-12-membered heterocycloalkyl moiety may not be directly bound to thecompound according to general formula (I) but may be connected theretothrough a —C₁-C₆-alkylene-linker. Said linker may be connected to acarbon ring atom or to a hetero ring atom of the 3-12-memberedheterocycloalkyl moiety. Examples include but are not limited to—CH₂-oxetane, —CH₂-pyrrolidine, —CH₂-piperidine, —CH₂-morpholine,—CH₂CH₂-oxetane, —CH₂CH₂-pyrrolidine, —CH₂CH₂-piperidine, and—CH₂CH₂-morpholine.

According to the invention, unless expressly stated otherwise, the3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered heterocycloalkylmoieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-,3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl,3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl,-tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.

According to the invention, “6-14-membered aryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring carbon atoms but no heteroatoms in the ring. Examples of preferred6-14-membered aryl moieties according to the invention include but arenot limited to benzene, naphthalene, anthracen, and phenanthren. The6-14-membered aryl moiety, which is bonded to the compound according tothe invention, in its periphery may optionally be condensed with a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 6-14-membered aryl moieties condensed with 3-12-memberedcycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indeneand tetraline, which in each case are connected through the6-14-membered aryl moiety. An example of a 6-14-membered aryl moietycondensed with a 3-12-membered heterocycloalkyl moiety includes but isnot limited to 1,2,3,4-tetrahydroquinoline, which is connected throughthe 6-14-membered aryl moiety. Examples of 6-14-membered aryl moietiescondensed with 5-14-membered heteroaryl moieties include but are notlimited to quinoline, isoquinoline, phenazine and phenoxacine, which ineach case are connected through the 6-14-membered aryl moiety.

According to the invention, the 6-14-membered aryl moiety may optionallybe connected through —C₁-C₆-alkylene-, i.e. the 6-14-membered arylmoiety may not be directly bound to the compound according to generalformula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 6-14-membered aryl moiety. Examplesinclude but are not limited to —CH₂—C₆H₅, —CH₂CH₂—C₆H₅ and —CH═CH—C₆H₅.

According to the invention, unless expressly stated otherwise, the6-14-membered aryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 6-14-membered aryl moietiesinclude but are not limited to 2-fluorophenyl, 3-fluorophenyl,2-methoxyphenyl and 3-methoxyphenyl.

According to the invention, “5-14-membered heteroaryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring atoms, wherein each cycle comprises independently of one another 1,2, 3, 4 or more heteroatoms independently of one another selected fromthe group consisting of nitrogen, oxygen and sulfur, whereas theremaining ring atoms are carbon atoms, and whereas bicyclic or tricyclicsystems may share common heteroatom(s). Examples of preferred5-14-membered heteroaryl moieties according to the invention include butare not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole,furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine,pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine,1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The5-14-membered heteroaryl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 5-14-membered heteroaryl moieties condensed with3-12-membered cycloalkyl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 5-14-membered heteroaryl moiety. Anexamples of a 5-14-membered heteroaryl moiety condensed with a3-12-membered heterocycloalkyl moiety includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 5-14-membered heteroaryl moiety. Examples of 5-14-memberedheteroaryl moieties condensed with 6-14-membered aryl moieties includebut are not limited to quinoline, isoquinoline, phenazine andphenoxacine, which in each case are connected through the 5-14-memberedheteroaryl moiety.

According to the invention, the 5-14-membered heteroaryl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 5-14-memberedheteroaryl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.Examples include but are not limited to —CH₂-oxazole, —CH₂— isoxazole,—CH₂-imidazole, —CH₂-pyridine, —CH₂-pyrimidine, —CH₂-pyridazine,—CH₂CH₂-oxazole, —CH₂CH₂-isoxazole, —CH₂CH₂-imidazole, —CH₂CH₂-pyridine,—CH₂CH₂-pyrimidine, and —CH₂CH₂-pyridazine.

According to the invention, unless expressly stated otherwise, the5-14-membered heteroaryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of 5-14-membered heteroaryl moieties includebut are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl,3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl,2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl,3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl,4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and2-methoxy-6-pyrazinyl.

Preferably, the compounds according to the invention have a structureaccording to general formula (I′)

wherein R¹ to R⁵, R⁷ to R²⁰, and X are defined as above, or aphysiologically acceptable salt thereof.

In one preferred embodiment, the excess of the cis-isomer so designatedis at least 50% de, more preferably at least 75% de, yet more preferablyat least 90% de, most preferably at least 95% de and in particular atleast 99% de.

In particularly preferred embodiments, the compound according to theinvention has a structure according to general formula (IX)

whereinR^(C) means —H or —OH;R^(D) means —H or —F;R⁵ means —H, —CH₃, or —CH₂CH₂—OH;R⁶ means —H or —CH₃; andR⁷ means —CH₃ and R⁸ means —CH₃; or R⁷ and R⁸ together with the carbonatom to which they are attached form a cyclopropyl ring.

When within the moiety corresponding to residue R⁴ the index is 1, thering is a cyclopropyl ring. When within the moiety corresponding toresidue R⁴ the index is 2, the ring is a cyclobutyl ring.

In a preferred embodiment, the compounds according to the invention arein the form of the free bases.

In another preferred embodiment, the compounds according to theinvention are in the form of the physiologically acceptable salts.

For the purposes of the description, a “salt” is to be understood asbeing any form of the compound in which it assumes an ionic form or ischarged and is coupled with a counter-ion (a cation or anion) or is insolution. The term is also to be understood as meaning complexes of thecompound with other molecules and ions, in particular complexes whichare associated via ionic interactions. Preferred salts arephysiologically acceptable, in particular physiologically acceptablesalts with anions or acids or also a salt formed with a physiologicallyacceptable acid.

Physiologically acceptable salts with anions or acids are salts of theparticular compound in question with inorganic or organic acids whichare physiologically acceptable, in particular when used in humans and/ormammals. Examples of physiologically acceptable salts of particularacids include but are not limited to salts of hydrochloric acid,sulfuric acid, and acetic acid.

The invention also includes isotopic isomers of a compound according tothe invention, wherein at least one atom of the compound is replaced byan isotope of the respective atom which is different from the naturallypredominantly occurring isotope, as well as any mixtures of isotopicisomers of such a compound. Preferred isotopes are ²H (deuterium), ³H(tritium), ¹³C and ¹⁴C.

Certain compounds according to the invention are useful for modulating apharmacodynamic response from one or more opioid receptors (mu, delta,kappa, NOP/ORL-1) either centrally or peripherally, or both. Thepharmacodynamic response may be attributed to the compound eitherstimulating (agonizing) or inhibiting (antagonizing) the one or morereceptors. Certain compounds according to the invention may antagonizeone opioid receptor, while also agonizing one or more other receptors.Compounds according to the invention having agonist activity may beeither full agonists or partial agonists.

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to a receptor but produce no regulatory effect, butrather block the binding of ligands to the receptor, are defined as“antagonists”.

In certain embodiments, the compounds according to the invention areagonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or deltaopioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.

The compounds according to the invention potently bind to the MOP and/orKOP and/or DOP and/or NOP receptors.

The compounds according to the invention can be modulators at the MOPand/or KOP and/or DOP and/or NOP receptors, and therefore the compoundsaccording to the invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, the compounds according to the invention areagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are agonists of the MOP and/or KOPand/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention areantagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are antagonists of the MOP and/orKOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) agonist activity atone or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) antagonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) agonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) antagonistactivity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the NOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the MOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        DOP receptor;    -   can be regarded as opioid pan agonists, i.e. have agonist        activity at the NOP receptor as well as agonist activity at the        MOP receptor as well as agonist activity at the KOP receptor as        well as agonist activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the KOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the KOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveagonist activity at the MOP receptor, agonist activity at the KOPreceptor, and antagonist activity at the DOP receptor. In someembodiments, preferably with respect to receptors of the peripheralnervous system, the compounds according to the invention

-   -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as agonist activity at the NOP        receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as antagonist activity at the NOP        receptor; or    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor, no significant activity at the NOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveantagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have antagonistactivity at the NOP receptor as well as agonist activity at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

For the purpose of the specification, “no significant activity” meansthat the activity (agonist/antagonist) of the given compound at thisreceptor is lower by a factor of 1000 or more compared to its activity(agonist/antagonist) at one or more of the other opioid receptors.

A further aspect of the invention relates to the compounds according tothe invention as medicaments.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of pain. A further aspect of theinvention relates to a method of treating pain comprising theadministration of a pain alleviating amount of a compound according tothe invention to a subject in need thereof, preferably to a human. Thepain is preferably acute or chronic. The pain is preferably nociceptiveor neuropathic.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of neurodegenerative disorders,neuroinflammatory disorders, neuropsychiatric disorders, and substanceabuse/dependence. A further aspect of the invention relates to a methodof treating any one of the aforementioned disorders, diseases orconditions comprising the administration of a therapeutically effectiveamount of a compound according to the invention to a subject in needthereof, preferably to a human.

Another aspect of the invention relates to a pharmaceutical compositionwhich contains a physiologically acceptable carrier and at least onecompound according to the invention.

Preferably, the composition according to the invention is solid, liquidor pasty; and/or contains the compound according to the invention in anamount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, basedon the total weight of the composition.

The pharmaceutical composition according to the invention can optionallycontain suitable additives and/or auxiliary substances and/or optionallyfurther active ingredients.

Examples of suitable physiologically acceptable carriers, additivesand/or auxiliary substances are fillers, solvents, diluents, coloringsand/or binders. These substances are known to the person skilled in theart (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetikand angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical composition according to the invention contains thecompound according to the invention in an amount of preferably from0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet morepreferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. %and in particular from 2.5 to 60 wt. %, based on the total weight of thepharmaceutical composition.

The pharmaceutical composition according to the invention is preferablyfor systemic, topical or local administration, preferably for oraladministration.

Another aspect of the invention relates to a pharmaceutical dosage formwhich contains the pharmaceutical composition according to theinvention.

In one preferred embodiment, the pharmaceutical dosage form according tothe invention is produced for administration twice daily, foradministration once daily or for administration less frequently thanonce daily. Administration is preferably systemic, in particular oral.

The pharmaceutical dosage form according to the invention can beadministered, for example, as a liquid dosage form in the form ofinjection solutions, drops or juices, or as a semi-solid dosage form inthe form of granules, tablets, pellets, patches, capsules,plasters/spray-on plasters or aerosols. The choice of auxiliarysubstances etc. and the amounts thereof to be used depend on whether theform of administration is to be administered orally, perorally,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or locally, forexample to the skin, the mucosa or into the eyes.

Pharmaceutical dosage forms in the form of tablets, dragees, capsules,granules, drops, juices and syrups are suitable for oral administration,and solutions, suspensions, readily reconstitutable dry preparations andalso sprays are suitable for parenteral, topical and inhalatoryadministration. Compounds according to the invention in a depot, indissolved form or in a plaster, optionally with the addition of agentspromoting penetration through the skin, are suitable percutaneousadministration preparations.

The amount of the compounds according to the invention to beadministered to the patient varies in dependence on the weight of thepatient, on the type of administration, on the indication and on theseverity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg,preferably from 0.001 mg/kg to 10 mg/kg, of at least one compoundaccording to the invention is administered.

Another aspect of the invention relates to a process for the preparationof the compounds according to the invention. Suitable processes for thesynthesis of the compounds according to the invention are known inprinciple to the person skilled in the art.

Preferred synthesis routes are described below:

The compounds according to the invention can be obtained via differentsynthesis routes. Depending on the synthesis route, differentintermediates are prepared and subsequently further reacted.

In a preferred embodiment, the synthesis of the compounds according tothe invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIa):

wherein R¹, R² and R³ are defined as above.

In another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of an intermediate according to generalformula (IIIb):

wherein R¹, R² and R³ are defined as above and PG is a protecting group.

Preferably the protecting group is -p-methoxybenzyl. Therefore, inanother preferred embodiment, the synthesis of the compounds accordingto the invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIc):

wherein R¹, R² and R³ are defined as above.

As already indicated, in general formula (IIIc), the -p-methoxybenzylmoiety represents a protecting group which can be cleaved in the courseof the synthesis route.

In yet another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of

-   -   an intermediate according to general formula (IIIa) and        according to general formula (IIIb); or    -   an intermediate according to general formula (IIIa) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIb) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIa), according        to general formula (IIIb) and according to general formula        (IIIc).

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

EXAMPLES

“RT” means room temperature (23±7° C.), “M” are indications ofconcentration in mol/l, “aq.” means aqueous, “sat.” means saturated,“sol.” means solution, “conc.” means concentrated.

Further Abbreviations

-   brine saturated aqueous sodium chloride solution-   CC column chromatography-   cHex cyclohexane-   DCM dichloromethane-   DIPEA N,N-diisopropylethylamine-   DMF N,N-dimethylformamide-   Et Ethyl-   ether diethyl ether-   EE ethyl acetate-   EtOAc ethyl acetate-   EtOH ethanol-   h hour(s)-   H₂O water-   HATU    O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   LDA Lithium-di-isoproyl-amid-   Me Methyl-   m/z mass-to-charge ratio-   MeOH methanol-   MeCN acetonitrile-   min minutes-   MS mass spectrometry-   NBS N-bromo-succinimide-   NEt₃ triethylamine-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   PE Petrol Ether (60-80° C.)-   RM reaction mixture-   RT room temperature-   T3P    2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide-   tBME tert-.butyl methyl ether-   THF tetrahydrofuran-   v/v volume to volume-   w/w weight to weight-   XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The yields of the compounds prepared were not optimised. Alltemperatures are uncorrected.

All starting materials, which are not explicitly described, were eithercommercially available (the details of suppliers such as for exampleAcros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge,Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® AvailableChemicals Database of MDL, San Ramon, US or the SciFinder® Database ofthe ACS, Washington D.C., US, respectively, for example) or thesynthesis thereof has already been described precisely in the specialistliterature (experimental guidelines can be found in the Reaxys® Databaseof Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS,Washington D.C., US, repspectively, for example) or can be preparedusing the conventional methods known to the person skilled in the art.

The mixing ratios of solvents or eluents for chromatography arespecified in v/v.

All the intermediate products and exemplary compounds were analyticallycharacterised by mass spectrometry (MS, m/z for [M+H]). In addition¹H-NMR and ¹³C spectroscopy was carried out for all the exemplarycompounds and selected intermediate products.

Remark Regarding Stereochemistry

CIS refers to the relative configuration of compounds described herein,in which both nitrogen atoms are drawn on the same face of thecyclohexane ring as described in the following exemplary structure. Twodepictions are possible:

TRANS refers to compounds, in which both nitrogen atoms are on oppositefaces of the cyclohexane ring as described in the following exemplarystructure. Two depictions are possible:

Synthesis of Intermediates Synthesis of INT-799:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaOH (1.42 g, 35.5 mmol) was added to a solution ofCIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere andthe reaction mixture was stirred at 80° C. for 30 min.((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was addedand stirring was continued for 2 days at 80° C. The reaction completionwas monitored by TLC. The reaction mixture was diluted with water (500mL) and extracted with diethyl ether (4×300 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (230-400mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford2.5 g (59%) ofCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(TLC system: 10% MeOH in DCM; Rf: 0.8).

Step 2:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

TFA (12 mL) was added toCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70°C. for 6 h. The reaction completion was monitored by LCMS. The reactionmixture was concentrated under reduced pressure. To the residue sat. aq.NaHCO₃ was added (until pH 10) and the organic product was extractedwith DCM (3×150 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (230-400 mesh silica gel; 5% MeOHin DCM as eluent) to afford 500 mg (33%) ofCIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]⁺ 358.2

Synthesis of INT-897:CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionicAcid

Step 1:CIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile

KOtBu (1.7 g, 15.23 mmol) was added to a suspension ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987) (1.3 g, 3.80 mmol) in DMSO (20 mL) at RT.3-Bromo-2,2-dimethylpropanenitrile (3.7 g, 28.84 mmol) was added and thereaction mixture was stirred for 16 h at 130° C. The reaction mixturewas quenched with cold water (25 mL) and the organic product wasextracted with EtOAc (2×20 mL). The combined organic extracts were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to give1.6 g ofCIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrileas a brown semi-solid. (TLC system: 10% MeOH in DCM; Rf: 0.6). Theproduct was used in the next step without further purification.

Step 2:CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionicAcid

12 N aq. HCl (16 mL) was added toCIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(1.6 g, 3.78 mmol) and the resulting solution was refluxed for 16 h. Thereaction mixture was concentrated under reduced pressure. To the residuetoluene was added and the resulting mixture was concentrated underreduced pressure again. The residue was washed with acetone (10 mL),diethyl ether (10 mL) and DCM (10 mL) to give 1.2 g ofCIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionicacid (INT-897) as a solid. (TLC system: 10% MeOH in DCM R_(f): 0.3.)[M+H]⁺442.3

Synthesis of INT-898:CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicacid; 2,2,2-trifluoro-acetic Acid Salt

Step 1:CIS-tert-butyl-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate

KOtBu (1M in THF) (13.74 mL, 13.74 mmol) was added to a solution ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987) (2.5 g, 9.16 mmol) in 1,4-dioxane (240 mL) under argonatmosphere and the reaction mixture was stirred for 15 minutes.Tert-butyl acrylate (1.60 mL, 10.99 mmol) in 1,4-dioxane (10 mL) wasadded. The reaction mixture was stirred for 1 h at RT, then quenchedwith sat. aq. NH₄Cl (60 mL) and the organic product was extracted withEtOAc (2×100 mL). The combined organic layer was dried over anhydr.Na₂SO₄ and concentrated in vacuo. The crude product was purified bycolumn chromatography (using 100-200 mesh silica gel and 0-10 vol % MeOHin DCM as eluent) to afford 1.2 g (32%) of tert-butylCIS-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoateas pale yellow solid (TLC system: 10% MeOH in DCM; Rf: 0.4).

Step 2:CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicacid; 2,2,2-trifluoro-acetic Acid Salt

CIS-tert-butyl-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate(44 mg) was treated with TFA (360 μL) at RT for 30 min. All volatileswere removed in vacuo. The residue was taken up in toluene andconcentrated under reduced pressure (3×) to yield3-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoic acid as the trifluoroacetic acid salt (INT-898) (54 mg).[M+H]f 414.3

Synthesis of INT-899:CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicAcid

Step 1: CIS-tert-butyl3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate

In analogy to the method described for INT-898 step 1CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)was converted into CIS-tert-butyl3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate.

Step 2:CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicAcid

A mixture of CIS-tert-butyl3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate(2.2 g, 5.486 mmol) and powdered NaOH (877 mg, 21.95 mmol) in toluene(40 mL) was stirred at 80° C. for 5 h under argon atmosphere. Toluenewas evaporated in vacuo. The resulting off-white solid was dissolved inDMSO (40 mL) under argon atmosphere at RT and powdered NaOH (877 mg,21.945 mmol) was added in one portion. The reaction mixture was stirredat 55° C. for 1 h. (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise over 5min. The reaction mixture was stirred for 1.5 h at 55° C. and a newportion of (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise over 5min. Stirring was continued at 55° C. for 18 h.(1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise over 5min and stirring was continued for 65 h at at 55° C. The reactionprogress was monitored by LCMS. DMSO was evaporated in vacuo. Theresulting crude product was dissolved in water (50 mL), the solution wascooled to 0° C. and neutralized with acetic acid. The excess water wasevaporated in vacuo and the residue was purified by columnchromatography (using 100-200 mesh silica gel and 0-10 vol % MeOH in DCMas an eluent) to get 450 mg ofCIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicacid (INT-899) contaminated with 4-methylbenzene-sulfonic acid (44% pureby LCMS) as a pale yellow solid. This material was used for followingreactions without additional purification. [M+H]430.3

Synthesis of INT-951:CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile

Step 1:1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) wasadded dropwise over 10 minutes at 0° C. The reaction mixture was allowedto stir at RT for 3 h, then quenched with water and the organic productwas extracted with ethyl acetate (3×200 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 5 g (crude) of1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrileas gummy brown liquid. The material was used for the next step withoutfurther purification.

Step 2:1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide

TFA (100 mL) was added to1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile(5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture wasstirred at RT for 2 days. The reaction mixture was concentrated invacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and theorganic product was extracted with dichloromethane (3×150 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 3.5 g (crude) of1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide. The material was used for the next step withoutfurther purification.

Step 3:1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutaneCarbonitrile

Thionyl chloride (35 mL) was added to1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide(3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at refluxfor 2 h. The reaction mixture was concentrated in vacuo. To the residuesat. aq. NaHCO₃ was added (until pH 10) and the organic product wasextracted with dichloromethane (3×150 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by column chromatography to afford 1.3 g (34% after threesteps) ofCIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile(INT-951). [M+H]⁺ 367.2.

Synthesis of INT-952:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (10 g, 25 mmol) in THF (500 mL) was added KOtBu (7.1 g, 63mmol) at 50° C. The reaction mixture was heated up to reflux,cyclobutylmethylbromide (11.3 g, 76 mmol) was added in one portion, andstirring was continued at reflux for 12 h. KOtBu (7.1 g) andcyclobutylmethylbromide (11.3 g) were added again. The reaction mixturewas allowed to stir another 2 h at reflux, then cooled to RT, dilutedwith water (150 mL) and the layers partitioned. The aqueous layer wasextracted with EtOAc (3×300 mL). The combined organic layers were driedover Na₂SO₄ and then concentrated in vacuo. The residue was filteredthrough a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture. Thefiltrate was concentrated in vacuo and the resulting solid wasrecrystallized from hot ethanol to yield 7.8 g ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-952). [M+H]⁺ 461.3.

Synthesis of INT-953:CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one

To a stirred solution of3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60%dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirredfor 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwiseand stirring was continued for 50 h. TLC analysis showed completeconsumption of the starting material. The reaction mixture was quenchedwith sat. aq. NH₄Cl (50 ml) and extracted with EtOAc (3×200 ml). Thecombined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. The resulting residue was purified columnchromatography (neutral aluminum oxide, EtOAc—petroleum ether (2:8)) togive1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4);R_(f)=0.48.

Step 2:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione

To a stirred solution of1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. Thereaction mixture was warmed up to RT and stirred for 16 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was quenched with sat. aq. NaHCO₃ (30 ml) and extracted withEtOAc (3×50 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, 230-400 mesh, EtOAc—pet ether(1:3)→(3:7)) to give1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4);R_(f)=0.40.

Step 3:1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol)and MeOH/H₂O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and thereaction mixture was stirred for 10 min at 0° C. (ice bath). A solutionof1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were addedand the reaction mixture was stirred at 45° C. for 20 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml),the combined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure to give1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1);R_(f)=0.45. The product was used for the next step without additionalpurification.

Step 4:CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containing1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, 2.81 mmol) was cooled in an ice bath (˜0° C.) and a solution ofphenylmagnesium bromide (26 ml, ˜2M in THF) was added slowly at 0° C.−5°C. The ice bath was removed and the reaction mixture was stirred for 30min, then diluted with sat. aq. NH₄Cl (25 ml) and extracted with EtOAc(4×30 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure to give pale yellow viscous oil.This residue was purified by column chromatography (silica gel, 230-400mesh, eluent: EtOAc—pet ether (15:85)→(2:4)) to giveCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(135 mg, 10%, white solid). TLC system: EtOAc—pet ether (1:1); R_(f)=0.6

Step 5:CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containingCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(130 mg, 0.25 mmol) was cooled in an ice bath and a mixture ofTFA/CH₂Cl₂ (2.6 ml, 1:1, v/v) was added slowly at 0° C.−5° C. Thereaction mixture was warmed to RT and stirred for 20 h, then quenchedwith methanolic NH₃ (10 ml, ˜10% in MeOH) and concentrated under reducedpressure to give pale yellow viscous oil. This residue was purifiedtwice by column chromatography (silica gel, 230-400 mesh, eluent:MeOH—CHCl₃ (1:99)→(2:98)) to give CIS—1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl₃ (5:95);R_(f)=0.25; [M+H]f 384.3

Synthesis of INT-958: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate

KOtBu (57.0 g, 508.4 mmol) was added to the solution of2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate(89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h atRT. The reaction mixture was quenched with sat. aq. NH₄Cl and extractedwith EtOAc (2×500 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 68.0g (60%; crude) of ethyl5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid(TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).

Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate(68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacialacetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to100° C. for 16 h. All volatiles were evaporated under reduced pressure.The residue was diluted with sat. aq. NaHCO₃ and extracted with ethylacetate (3×300 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 44.0g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as abrown solid (TLC system: 50% ethyl acetate in pet ether; Rf: 0.45).[M+H]⁺ 201.1

Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958)(44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h usingDean Stark apparatus. All volatiles were evaporated under reducedpressure. The residue was diluted with sat. aq. NaHCO₃ and extractedwith ethyl acetate (3×300 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toafford 45.0 g (85%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a lightbrown solid (TLC system: 50% ethyl acetate in petroleum ether; Rf:0.55).

Step 2: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide

Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H₂O₂ (210.0 mL,1844.2 mmol) were added to the solution of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g,184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture wasstirred at RT for 14 h. The reaction mixture was diluted with water (1.5L) and stirred for 1 h. The precipitated solid was separated byfiltration, washed with water, petroleum ether and dried under reducedpressure to get 32.0 g (66%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a whitesolid. (TLC system: 10% MeOH in DCM R_(f): 0.35).

Step 3: methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate

A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide(25.0 g, 95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL,477.09 mmol) and KF—Al₂O₃ (125.0 g) in methanol (500 mL) was heated to80° C. for 16 h. The reaction mixture was filtered through celite andthe solid residue was washed with methanol. The combined filtrate wasconcentrated under reduced pressure. The residue was diluted with waterand extracted with ethyl acetate (3×500 mL). The combined organic layerwas washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to afford 18.0 g (66%) of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brownsolid. (TLC system: 5% MeOH in DCM R_(f): 0.52.)

Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine

A suspension of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. Thereaction mixture was filtered through celite pad, the solid residue waswashed with water and the combined filtrate was extracted with EtOAc(4×200 mL). The combined organic layer washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to afford 12.5 g (88%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brownsemi-solid. (TLC system: 5% MeOH in DCM R_(f): 0.22.).

Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to asolution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g,53.418 mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) inacetonitrile (130 mL) at 0° C. The reaction mixture was warmed up toroom temperature and stirred for 16 h. The reaction mixture was quenchedwith sat. aq. NH₄Cl and concentrated under reduced pressure. The residuewas dissolved in water and extracted with EtOAc (3×200 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to afford 10.5 g (72%) of4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a lightbrown solid. (TLC system: 5% MeOH in DCM R_(f): 0.32.). [M+H]⁺ 219.1

Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one

Step 1: 8-(Dimethylamino)-1,4-dioxaspiro 4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solutionof 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL)at RT under argon atmosphere. The solution was stirred for 10 min and 40wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) weresequentially added. The reaction mixture was stirred for 48 h at RT,then diluted with water (100 mL) and extracted with EtOAc (2×200 mL).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 44 g of8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%) as awhite solid.

Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine

8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167mol) in THF (350 mL) was added to the solution of 3M phenylmagnesiumbromide in diethyl ether (556 mL, 1.67 mol) dropwise at −10° C. underargon atmosphere. The reaction mixture was stirred for 4 h at −10° C. to0° C. and then at RT for 18 h. The reaction completion was monitored byTLC. The reaction mixture was cooled to 0° C., diluted with sat. aq.NH₄Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 60 g of, NN-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]-decan-8-amine as a liquid.

Step 3: 4-(dimethylamino)-4-phenylcyclohexanone

A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h andthen at RT for 18 h. The reaction completion was monitored by TLC. Thereaction mixture was extracted with DCM (2×150 mL). The aqueous layerwas basified to pH 10 with solid NaOH and extracted with ethyl acetate(2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The solid residue was washedwith hexane and dried in vacuo to afford 7 g of4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps)as a brown solid. [M+H]⁺ 218.1

Synthesis of INT-966:3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione

KCN (93.8 g, 1441.6 mmol) and (NH₄)₂CO₃ (271.8 g, 1729.9 mmol) wereadded to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961mmol) in MeOH:H₂O (1:1 v/v) (1.92 L) at RT under argon atmosphere. Thereaction mixture was stirred at 60° C. for 16 h. The reaction completionwas monitored by TLC. The reaction mixture was cooled to 0° C., theprecipitated solid was filtered off and dried in vacuo to afford 120 g(55%) of9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione. Thefiltrate was extracted with DCM (2×1.5 L). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford additional 30 g (14%) of9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}5]tetradecane-1,3-dione (TLCsystem: 10% Methanol in DCM; Rf: 0.4).

Step 2:2-[(4-Methoxyphenyl)-ethyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione

Cs₂CO₃ (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g,663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reactionmixture was stirred for 30 min. A solution of p-methoxybenzyl bromide(96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RTfor 48 h. The reaction completion was monitored by TLC. The reactionmixture was quenched with sat. aq. NH₄Cl (1.0 L) and the organic productwas extracted with EtOAc (2×1.5 L). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was washed with diethyl ether and pentane and dried underreduced pressure to afford 151 g (65%) of2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dioneas an off white solid (TLC system: 10% MeOH in DCM; Rf: 0.6).

Step 3:2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one

AlCl₃ (144.3 g, 1082.6 mmol) was added to a solution of LiAlH₄ (2M inTHF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argonatmosphere and the resulting mixture was stirred at RT for 1 h.2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione (150 g,433.05 mmol) was added at 0° C. The reaction mixture was stirred at RTfor 16 h. The reaction completion was monitored by TLC. The reactionmixture was cooled to 0° C., quenched with sat. aq. NaHCO₃ (500 mL) andfiltered through celite pad. The filtrate was extracted with EtOAc(2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo to afford 120 g (84%) of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-oneas an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.5).

Step 4: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

A solution of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one(120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 hand then at RT for 18 h. The reaction completion was monitored by TLC.The reaction mixture was extracted with DCM (2×2.0 L). The aqueous layerwas basified to pH 10 with 50% aq. NaOH and then extracted with DCM(2×2.0 L). Combined organic extracts were dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The solid residue was washedwith hexane and dried in vacuo to afford 90 g of3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione(INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4)[M+H]⁺ 289.11.

Synthesis of INT-971:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-968) was converted intoCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

TFA (0.2 mL) was added to the solution ofCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one(300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 3 h. The reaction completion was monitored by TLC.The reaction mixture was quenched with sat. aq. NaHCO₃ and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification of the residue by preparative TLC (3% MeOH in DCMas mobile phase) yielded 50 mg (18%) ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-971) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20)[M+H]⁺ 478.3

Synthesis of INT-974:CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solutionof 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione(INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argonatmosphere. The solution was stirred for 15 min and 40 wt % aq.dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentiallyadded. The reaction mixture was stirred for 48 h and the completion ofthe reaction was monitored by NMR. The reaction mixture was diluted withwater (1.0 L) and the organic product was extracted with ethyl acetate(2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford 90 g (85%) of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrileas an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf:0.35, 0.30).

Step 2:CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17 mmol) wasadded dropwise to a solution of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. Thereaction mixture was stirred for 16 h at RT. The reaction completion wasmonitored by TLC. The reaction mixture was cooled to 0° C., quenchedwith sat. aq. NH₄Cl (200 mL) and the organic product was extracted withEtOAc (2×200 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The reaction was carriedout in 4 batches (15 g×2 and 5 g×2) and the batches were combined forpurification. Purification of the crude product by flash columnchromatography on silica gel (230-400 mesh) (2 times) (0-20% methanol inDCM) eluent and subsequently by washing with pentane yielded 5.6 g (11%)ofCIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-974) as an off-white solid. (TLC system: 5% MeOH in DCM in presenceof ammonia; Rf: 0.1). [M+H]⁺ 412.2

Synthesis of INT-975:CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reactionmixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30mmol) was added and stirring was continued at RT for 4 h. The reactioncompletion was monitored by TLC. The reaction mixture was diluted withsat. aq. NH₄Cl (150 mL) and the organic product was extracted with EtOAc(2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo. The reaction was carried out in 2 batches (8g×2) and the batches were combined for purification. Purification of thecrude product by flash column chromatography on silica gel (0-10%methanol in DCM) and subsequently by washing with pentane yielded 11 g(47%) ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) as a white solid. [M+H]⁺ 394.2

Synthesis of INT-976:CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2g, 9.22 mmol) was suspended in 40 mL EtOH/H₂O (1:1 v/v) at RT underargon atmosphere. (NH₄)₂CO₃ (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22mmol) were added. The reaction mixture was stirred at 60° C. for 18 h.The reaction mixture was cooled to 0° C. and diluted with ice-water andfiltered through a glass filter. The solid residue was dried underreduced pressure to afford8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g,86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf:0.25).

Step 2: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one

LiAlH₄ (2M in THF) (70 mL, 139.4 mmol) was added to the solution of8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g,34.8 mmol) in THF/Et₂O (2:1 v/v) (400 mL) at 0° C. under argonatmosphere. The reaction mixture was stirred for 4 h at 60° C. Thereaction completion was monitored by TLC. The reaction mixture wascooled to 0° C., quenched with saturated Na₂SO₄ solution (100 mL) andfiltered through Celite pad. The filtrate was dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford 5.7 g (59%) of8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one as an offwhite solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).

Step 3: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A mixture of CIS— andTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g,29.30 mmol) was purified by preparative chiral SFC (column: ChiralcelAS-H, 60% CO₂, 40% (0.5% DEA in MeOH)) to get 5 g ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) asa white solid. [M+H]⁺ 274.2.

Synthesis of INT-977:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic Acid Salt

Step 1:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticAcid Tert-Butyl Ester

A solution ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooled to 0° C. andtreated with LDA solution (2M in THF/heptane/ether, 25.4 mL, 50.8 mmol).The resulting mixture was allowed to warm up to RT over 30 min. Thesolution was then cooled to 0° C. again and tert-butyl-bromoacetate(5.63 mL, 38.1 mmol) was added. The reaction mixture was stirred at RTfor 16 h, quenched with water and extracted with DCM (3×). The combindedorganic layers were dried over Na₂SO₄, filtered and concentrated inderreduced pressure. Purification of the residue by column chromatographyon silica gel providedCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (4.4 g).

Step 2:cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticAcid Trifluoroacetic Acid Salt

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) andheated to reflux overnight. After cooling to RT all volatiles areremoved in vacuo. The residue was taken up in THF (lmL) and addeddropwise to diethyl ether (20 mL). The resulting precipitate wasfiltered off and dried under reduced pressure to giveCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a whitesolid. [M+H]⁺ 332.2

Synthesis of INT-978:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide

CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) wasdissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol),dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) weresequentially added. The reaction mixture was stirred at RT overnight,then diluted with 1 M aq. Na₂CO₃ (5 mL). The aqueous layer was extractedwith DCM (3×5 mL), the combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel to yieldCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide(INT-978) (39 mg) as a white solid. [M+H]⁺ 359.2

Synthesis of INT-982:CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RTfor 10 min.CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for15 min. 1-(Bromomethyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) wasadded at 0° C. The reaction mixture was heated to 60° C. for 16 h. Aftercooling down to RT, water (100 mL) was added and the mixture wasextracted with DCM (3×150 mL). The combined organic layers were washedwith water (70 mL), brine (100 mL), dried over Na₂SO₄ and concentratedunder reduced pressure. Purification of the residue by columnchromatography on silica gel providedCIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(6.5 g) as a light yellow solid.

Step 2:CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To the solution ofCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65 mL) and theresulting mixture was stirred at RT for 16 h. The reaction mixture wasconcentrated under reduced pressure. The residue was taken up in DCM(100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH 10. Theorganic layer was separated and washed with brine (40 mL), dried overMgSO₄, filtered and concentrated under reduced pressure. Crystallizationof the residue from EtOAc providedCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-982) (3.41 g) as an off-white solid. [M+H]⁺ 356.3

Synthesis of INT-984:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) was converted intoCIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas converted intoCIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-984).

Synthesis of INT-986:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. Thereaction mixture was basified with 2N aq. NaOH to pH-10 and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL)and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with5N aq. NaOH to pH-10 and extracted with DCM (3×10 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuoto give 3.5 g (crude) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneas semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.60.).

Step 2:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to thesolution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) andacetic acid (0.5 mL) in methanol (20 mL). The reaction mixture wasstirred at RT for 3 h, then quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (3×50 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g(62%) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneas a solid. (TLC system: 50% EtOAc in Pet. Ether; R_(f): 0.65).

Step 3:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986)

Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia(˜25 mL) at −78° C. The resulting mixture was stirred for 10 min at −78°C. A solution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reactionmixture was stirred for 15 min, then quenched with sat. aq. NH₄Cl,warmed to RT and stirred for 1 h. The organic product was extracted withDCM (3×50 mL). The combined organic layer was washed with water, brineand concentrated under reduced pressure to afford 1.30 g (72%) ofCIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM R_(f):0.15.). [M+H]⁺ 356.3

Synthesis of INT-987:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method as described for INT-982 step 2CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-952) was converted intoCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987).

Synthesis of INT-1008:CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amineHydrochloride (INT-1004)

A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0eq.) and 2M solution of EtNH₂ in THF (200 ml, 2.5 eq. 400.64 mmol) inEtOH (30 mL) was stirred at RT for 48 h. The reaction mixture wasconcentrated under argon atmosphere. The residue was diluted with ether(60 mL) and added to the freshly prepared PhLi solution [prepared byaddition of 2.5M n-BuLi in THF (70.5 mL, 1.1 eq. 176.27 mmol) to asolution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100mL) at −30° C. and stirred at RT for 1 h] at RT. The reaction mixturewas stirred at RT for 1.5 h, then cooled down to 0° C. and quenched withsat. aq. NH₄Cl (100 mL). The resulting mixture was extracted with EtOAc(2×750 mL), combined organic extracts were washed with water (3×350 mL),brine (300 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The crude product was dissolved in ethylmethyl ketone (100 mL)and TMSCl (37.5 mL) was added at 0° C. The reaction mixture was stirredat RT for 16 h, the precipitate formed was filtered off and washed withacetone and THF to giveethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as anoff-white solid. This reaction was done in 2 batches of 25 g scale andthe yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575mmol). LCMS: m/z 262.2 (M+H)⁺.

Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)

To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-aminehydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 mL) was addedconc. HCl (62.5 mL) at 0° C. and the reaction mixture was stirred at RTfor 16 h. The reaction mixture was basified with 1N aq. NaOH to pH ˜14at 0° C. and extracted with DCM (2×750 mL). Organic layer was washedwith water (400 mL), brine (400 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanonewhich was used in the next step without further purification. Thisreaction was carried out in another batch of 15.1 g scale and yield isgiven for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).

Step 4: mixture of CIS— andTRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(INT-1006 and INT-1007)

To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol,1.0 eq.) in EtOH (250 mL) and water (200 mL) was added (NH₄)₂CO₃ (18.8g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for15 min. KCN (5.09 g, 78.341 mmol, 1.0 eq.) was and the resulting mixturewas stirred at 60° C. for 18 h. The reaction mixture was cooled to RT,the precipitate was filtered off, washed with water (250 mL), EtOH (300mL), hexane (200 mL) and dried under reduced pressure to yield CIS— andTRANS-mixture 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(13.0 g, 45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296mmol). LC-MS: m/z [M+]⁺=288.2.

Step 5: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(INT-1006)

To a solution of cis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) inMeOH/DCM (1:1 v/v, 960 mL) was added a solution of L-tartaric acid inMeOH (25 mL). The resulting mixture was stirred at RT for 2 h and thenkept in refrigerator for 16 h. The solid material was filtered off andwashed with MeOH/DCM (1:5, 50 ml) to get8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate (7.5g) as a white solid. The solid was suspended in sat. aq. NaHCO₃ (pH-8)and the resulting mixture was extracted with 25% MeOH-DCM (2×800 ml).Combined organic extracts were washed with water (300 ml), brine (300ml) and dried over anhydrous Na₂SO₄. The solvent was evaporated underreduced pressure and the residue was triturated with 20% DCM-hexane toafford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione asa white solid. This step was done in 2 batches (12 g & 2.4 g) and yieldis given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol).LC-MS: m/z [M+1]⁺=288.0.

Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(INT-1008)

To a slurry of LiAlH₄ (793 mg, 20.905 mmol, 3.0 eq.) in THF (15 mL) wasadded a suspension ofcis-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g,6.968 mmol, 1.0 eq.) in THF (60 mL) at 0° C. and the reaction mixturewas stirred at 65° C. for 16 h. The resulting mixture was cooled to 0°C., quenched with sat. aq. Na₂SO₄ (20 ml), stirred at RT for 1 h andfiltered through celite. The celite layer was washed with 15% MeOH-DCM(500 ml). The combined filtrate was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude product wastriturated with 15% DCM-Hexane to affordCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)(1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol).LC-MS: m/z [M+H]⁺=274.2.

Synthesis of INT-1026:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide

Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) atRT and the reaction mixture was stirred at RT for 18 h. The reactionmixture was cooled to 0° C. and quenched by dropwise addition of sat.aq. NaHCO₃ (500 mL) over a period of 30 min. The organic product wasextracted with EtOAc (3×100 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 10 g(crude) of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide asa white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).

Step 2:2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide

Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwiseto a solution of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. Thereaction mixture was stirred for 2 h at −10° C. to 0° C. The reactioncompletion was monitored by TLC. The reaction mixture was quenched withsat. aq. NH₄Cl (50 mL) at 0° C. and the organic product was extractedwith EtOAc (3×100 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate inhexane) to yield 6.0 g (46%) of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamideas a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).

Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine Hydrochloride

2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added toa solution of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide(6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h. The reaction mixture was concentrated in vacuo.The residue was washed with diethyl ether to yield 3 g (crude) of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid(TLC system: 5% MeOH in DCM; R_(f): 0.10).

Step 4:8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine

Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo at 30° C. and to the residue sat. aq. NaHCO₃ was added. Theorganic product was extracted with DCM (3×30 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and solvent was concentratedunder reduced pressure to get 3 g (crude) of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).

Step 5:N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)

Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo and to the residue sat. aq. NaHCO₃ was added. The organic productwas extracted with DCM (3×30 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and solvent was concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) ofN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).

Step 6:4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone

5% sulfuric acid in water (25 mL) was added toN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RTfor 24 h. The reaction mixture was quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (2×50 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo toafford 2.0 g (crude) of4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as athick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).

Step 7:8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone(1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H₂O (1:1 v/v) at RTunder argon atmosphere. (NH₄)₂CO₃ (1.9 g, 13.05 mmol) and KCN (0.34 g,5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16h. The reaction mixture was diluted with ice-water and the organicproduct was extracted with DCM (2×50 mL). The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated in vacuo to give 1.0 g(crude) of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dioneas a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).

Step 8:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

Diastereomeric mixture of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(1.0 g) was separated by reverse phase preparative HPLC to afford 400 mgof isomer 1(CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 60 mg of isomer 2(TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 300 mg of mixture of both isomers. Reverse phase preparative HPLCconditions: mobile phase: 10 mM ammonium bicarbonate inH₂O/acetonitrile, column: X-BRIDGE-C₁₈ (150*30), 5 μm, gradient (T/B %):0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min,diluent: mobile phase+THF.

Step 9:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026)

LiAlH₄ (1M in THF) (4.48 mL, 4.48 mmol) was added to a solution ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(isomer-1) (0.4 g, 1.12 mmol) in THF:Et₂O (2:1 v/v, 15 mL) at 0° C.under argon atmosphere. The reaction mixture was stirred at 65° C. for16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄(1000 mL) and filtered through celite pad. The filtrate was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) toyield 0.3 g (78%) ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf:0.2). LC-MS: m/z [M+1]⁺=344.2.

Synthesis of INT-1031:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-952CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-974) was converted intoCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 21-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-onewas converted into1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1031).

Synthesis of INT-1037:8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one

Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400mL) and the suspension was cooled to 0° C.8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg,0,261 mmol) (step 1 of INT-965) was added portionwise at 0° C. Thereaction mixture was stirred 1.5 h at 0° C., then overnight at RT andthen 2 h at 40° C. The reaction mixture was cooled down to 0° C.,quenched carefully with sat. aq. Na₂SO₄, EtOAc (400 mL) was added andthe resulting mixture was stirred for 2 h and then left without stirringfor 2 h at RT. The precipitate was filtered off and washed with EtOAcand MeOH. The resulting solid residue was suspended in methanol andstirred at RT overnight. The precipitate was filtered off and disposed.The filtrate was concentrated under reduced pressure, the residue wassuspended thoroughly in water (50 mL) at 40° C., the precipitate wasfiltered off and dried under reduced pressure to yield9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one (11.4 g,41%). Mass: m/z 213.2 (M+H)⁺.

Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione

In analogy to the method described for INT-1003 step 39,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one was treatedwith conc. aq. HCl to be converted into1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H)⁺.

Step 3: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037)

In analogy to the method described for INT-965 step 11,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine andpotassium cyanide to be converted into8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037). Mass: m/z 223.2 (M+H)⁺.

Synthesis of INT-1038:CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one

To the suspension of8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1Mbromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and thereaction mixture was stirred for 1 h at RT. Additional portion of 1Mbromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. Thereaction mixture was stirred at RT overnight, then quenched withmethanol/water. Solid NH₄Cl and DCM were added to the resulting mixtureand the precipitate was filtered off. The organic phase of the filtratewas separated and the aqueous phase was extracted with DCM (3×). Thecombined organic phases were dried over anhydr. Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (DCM/MeOH, 100/0 to 65/35) to yieldCIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)⁺.

Synthesis of INT-1059:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added(NH₄)₂CO₃ (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture wasstirred at RT for 15 min. KCN (74.92 g, 1.15 mol, 1.0 eq.) was added.The reaction mixture was stirred at 60° C. for 18 h and then filtered inhot condition to get white solid which was washed with water (2.5 L),ethanol (1 L) and hexane (2.5 L). The resulting solid was dried underreduced pressure to getCIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223g, 0.776 mol, 65%) as a white solid. The filtrate was collected frommultiple batches (˜450 g) which contained a mixture of cis and transisomers. The filtrate was concentrated under reduced pressure and solidobtained was filtered and washed with water (1 L) and hexane (1 L).Solid material was dried under reduced pressure to get ˜100 g of amixture of cis and trans (major) isomers. Crude material was partiallydissolved in hot MeOH (600 mL) and cooled to RT, filtered throughsintered funnel, washed with MeOH (200 mL) followed by ether (150 mL)and dried to getTRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50g, 0.174 mmol, ˜9-10%).

Step 2: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059)

In analogy to the method described for INT-976 step 2TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione wastreated with LiAlH₄ to be converted intoTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059). Mass: m/z 274.2 (M+H)⁺.

Synthesis of INT-1068 and INT-1069: CIS— andTRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g,230.096 mmol) in MeOH (400 mL) was added NH₄Cl (24.6 g, 460.8 mmol)followed by NH₄OH (400 mL) at RT and the reaction mixture was stirredfor 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resultingmixture was stirred for 16 h at RT. The reaction mixture was extractedwith DCM (3×750 mL). Combined organic layer was washed with water (750mL), brine (750 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was triturated with DCM/hexane to get crude1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) asan off white solid which was used in next step without furtherpurification. LC-MS: m/z [M+H]⁺=244.2 (MW calc. 244.09).

Step 2:N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide

To a solution of1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol,3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P(18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirredat RT for 16 h, then diluted with water (100 ml) and extracted with 10%MeOH in DCM (2×250 mL). Combined organic layer was washed with brine(100 mL), dried over Na₂SO₄ and concentrated under reduced pressure toget crudeN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamideas a light yellow sticky material which was used in the next stepwithout further purification. LC-MS: m/z [M+1]⁺=339.9 (MW calc. 339.36).

Step 3:1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

To suspension of LiAlH₄ (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40mL) was addedN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide(6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. Thereaction mixture was stirred at RT for 16 h, then quenched with sat. aq.Na₂SO₄ at 0° C., excess THF was added and the resulting mixture wasstirred at RT for 2 h. The resulting suspension was filtered throughcelite and the filter cake was washed with 10% MeOH in DCM (150 mL).Combined filtrate was concentrated under reduced pressure to yield crude1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, crude) as a light yellow sticky material which was directly usedin the next step without further purification. LC-MS: m/z [M+1]⁺=330.0(MW calc. 329.40).

Step 4: CIS— andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068 and INT-1069)

To a solution of1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g,76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition ofCOC1₂ (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. andstirred at RT for 16 h. Reaction mixture was basified with sat NaHCO₃solution and extracted with DCM (2×200 ml). Combined organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to get crudeproduct which was purified by prep HPLC to getCIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068) (1.5 g) (major isomer, polar spot on TLC) andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% byHPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1]⁺=356.2 (MWcalc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5 g,Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1ml/min, R_(t)=5.17 min. ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm)=7.43-7.27 (m,5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz),1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).

Synthesis of INT-1075:CIS-3-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanoicacid

A mixture ofCIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionitrile(INT-790) (2.8 g, 6.39 mmol, 1.0 eq.) and NaOH (1.02 g, 25.57 mmol, 4.0eq.) in ethylene glycol/water (3:1; 20 mL) was stirred at 110° C. for 36h. The reaction mixture was acidified with aq. NaHSO₄, the precipitatewas filtered off and purified by column chromatography (silica gel; 8%MeOH/DCM) to yieldCIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionicacid (1.0 g, 2.188 mmol, 34%) as an off-white solid. LC-MS): m/z[M+1]⁺=458.0 (MW calc.=457.61).

For further intermediates the synthesis in analogy to previouslydescribed methods is given in the following table. The syntheses of thebuilding blocks and intermediates have either been described previouslywithin this application or can be performed in analogy to the hereindescribed methods or by methods known to the person, skilled in the art.Such a person will also know which building blocks and intermediatesneed to be chosen for synthesis of each exemplary compound.

m/z Inter- in analogy [M + mediate Chemical Name Chemical Structure tomethod H]⁺ INT-790 CIS-3-[8-Dimethylamino- 1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan- 3-yl]-2,2-dimethyl-propionitrile

INT-897 Step 1 439.3 INT-791 CIS-3-[l-(Cyclobutyl-methyl)-8-(ethyl-methyl- amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan- 3-yl)-2,2-dimethyl- propionitrile

INT-897 Step 1 437.3 INT-792 CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile

INT-897 Step 1 413.3 INT-793 CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile

INT-897 Step 1 427.3 INT-794 CIS-3-(3,4- dimethoxybenzyl)-8-(dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one

INT-975 424.3 INT-796 CIS-8-Dimethylamino-3- [(4-methoxyphenyl)-methyl]-8-(3-methoxy- propyl)-1,3-diazaspiro[4.5] decan-2-one

INT-974 390.3 INT-797 CIS-8-(Ethyl-methyl- amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

INT-976 288.2 INT-894 CIS-3-[l-(Cyclobutyl- methyl)-8-[methyl-(2-methyl-propyl)-amino]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-propionic acid; 2,2,2- trifluoro-acetic acid salt

INT-898 456.3 INT-895 CIS-3-[8-Dimethylamino- 1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- propionic acid; 2,2,2-trifluoro-acetic acid salt

INT-898 404.2 INT-896 CIS-3-[8-Dimethylamino- 1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- propionic acid; 2,2,2-trifluoro-acetic acid salt

INT-898 418.3 INT-949 CIS-8-Dimethylamino-1- ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

INT-984 302.2 INT-950 CIS-1-(Cyclobutyl- methyl)-8-dimethylamino-8-phenyl-3-[phenyl- methyl]-1,3-diazaspiro[4.5] decan-2-one

INT-952 432.3 INT-954 4-Dimethylamino-4-(5- methyl-thiophen-2-yl)-cyclohexan-1-one

INT-965 238.1 INT-955 4-Dimethylamino-4- thiophen-2-yl-cyclohexan- 1-one

INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3- yl)-4-oxo-cyclohexane-1-carbonitrile

INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1-carbonitrile

INT-958 202.1 INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3-yl)-cyclohexan-1-one

INT-961 222.2 INT-960 4-Dimethylamino-4- pyrazin-2-yl-cyclohexan-1- one

INT-961 220.1 INT-962 4-Dimethylamino-4-(3- methoxyphenyl)-cyclohexan-1-one

INT-965 248.2 INT-963 CIS-3-Benzyl-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one

INT-975 364.2 INT-964 4-(Ethyl-methyl-amino)-4- phenyl-cyclohexan-1-one

INT-965 232.2 INT-967 CIS-8-Dimethylamino-8- [4-(methoxymethyloxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one

INT-974 454.3 INT-968 CIS-8-Dimethylamino-8- [3-(methoxymethyloxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one

INT-974 454.3 INT-969 CIS-1-(Cyclobutyl- methyl)-8-dimethylamino-8-(4-hydroxyphenyl)-3- [(4-methoxyphenyl)- methyl]-1,3-diazaspiro[4.5]decan-2-one

INT-971 478.3 INT-970 CIS-8-Dimethylamino-8- (4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one

SC_2017 424.3 INT-972 CIS-8-Dimethylamino-8- (3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one

SC_2017 424.3 INT-973 CIS-8-Dimethylamino-8- (4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one

INT-974 412.2 INT-979 CIS-8-Dimethylamino-1- (3-methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5] decan-2-one

INT-984 346.2 INT-980 CIS-8-Dimethylamino-1- (2-methoxy-ethyl)-8-phenyl-1,3-diazaspiro[4.5] decan-2-one

INT-984 332.2 INT-981 CIS-8-Dimethylamino-8- phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one

INT-984 316.2 INT-983 CIS-1-(Cyclopropyl- methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-984 328.2 INT-985 CIS-1-(Cyclobutyl- methyl)-8-(methyl-propyl-amino)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-986 370.3 INT-993 4-benzyl-4-(dimethylamino) cyclohexanone

INT-965 232.3 INT-994 CIS-8-benzyl-8- (dimethylamino)-1,3-diazaspiro[4.5]decan-2-one

INT-976 288.2 INT-995 TRANS-8-benzyl-8- (dimethylamino)-1,3-diazaspiro[4.5]decan-2-one

INT-976 288.2 INT-997 CIS-8-(dimethylamino)-8- (thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one

INT-976 280.1 INT-998 TRANS-8-(dimethylamino)- 8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one

INT-976 280.1 INT-999 4-(dimethylamino)-4-(1- methyl-1H-benzo[d]imidazol-2-yl) cyclohexanone

INT-965 272.2 INT-1000 CIS-8-(dimethylamino)-8- (1-methyl-1H-benzo[d]imidazol-2-yl)-1,3- diazaspiro[4.5]decan-2-one

INT-976 328.2 INT-1001 TRANS-8-(dimethylamino)- 8-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,3- diazaspiro[4.5]decan- 2-one

INT-976 328.2 INT-1009 TRANS-8-ethylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one

INT-1008 274.2 INT-1013 CIS-3-(1- (cyclobutylmethyl)- 2-oxo-8-phenyl-8-(propylamino)-1,3- diazaspiro[4.5]decan- 3-yl)-2,2-dimethylpropanenitrile

SC_5068 437.3 INT-1024 CIS-8-(dimethylamino)-8- (3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

INT-977 (step 2) 292.2 INT-1025 CIS-8-(dimethylamino)-8-(4-fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one

INT-974, INT-977 (step 2) 292.2 INT-1039 CIS-8-(dimethylamino)-8-(3-(trifluoromethoxy) phenyl)-1,3-diazaspiro[4.5] decan-2-one

INT-1038 358.2 INT-1040 (CIS)-8-(dimethylamino)- 8-(3-(trifluoromethyl)phenyl)-1,3-diazaspiro[4.5] decan-2-one

INT-1038 342.2 INT-1041 (CIS)-8-(dimethylamino)-8-(3-methoxyphenyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1038 304.2 INT-1042 (CIS)-8-(5-chlorothiophen-2-yl)-8-(dimethylamino)- 1,3-diazaspiro[4.5]decan- 2-one

INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)- 8-(3-fluoro-5-methylphenyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)- 8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one

INT-1038 308.2 INT-1047 (CIS)-8-(methyl(oxetan-3-ylmethyl)amino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one

INT-1026 330.5 INT-1061 TRANS-1-(cyclopropyl- methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5] decan-2-one

INT-984 328.2 INT-1063 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1031 346.2 INT-1066 TRANS-1- (cyclobutylmethyl)-8-(dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one

INT-987 342.3 INT-1070 CIS-8-(dimethylamino)-8- phenyl-1-(3,3,3-trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1068 360.2 INT-1074 CIS-8-(dimethylamino)-8- (3-fluorophenyl)-1-((1-hydroxycyclobutyl) methyl)-1,3-diazaspiro[4.5] decan-2-one

INT-1031 376.2

Synthesis of Exemplary Compounds Synthesis of SC_5003:CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide

Into a dry tube were added successively 1 mL of a solution ofCIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicacid trifluoroacetate (INT-898) (0.1 M in DCM), 2 mL of a solution of2-methoxypyridin-4-amine (0.2 M in DCM), 0.07 mL of triethylamine and0.118 mL T3P (1.7 M, 50% in ethyl acetate). The reaction mixture wasstirred at RT overnight, quenched with 3 mL 1M aq. Na₂CO₃ and stirred atRT for 1 h. The organic layer was separated and the aqueous layer wasextracted with DCM (2×). The combined organic layers were concentratedunder reduced pressure and the product was purified by HPLC to obtainCIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide(SC_5003). [M+H]⁺ 520.3

Synthesis of SC_5022:CIS—N-(2-cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide

CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide(SC_5002) (0.270 g, 0.631 mmol) was dissolved in 1,4 dioxane (30 mL) atRT and purged with nitrogen. To the reaction mixture were added5-bromopyrimidine-2-carbonitrile (0.173 g, 0.946 mmol), Cs₂CO₃ (0.410 g,1.262 mmol), Xanthphos (0.055 g, 0.095 mmol), Pd₂(dba)₃ (0.029 g, 0.032mmol) and the resulting suspension was again purged with nitrogen for 15minutes. The reaction mixture was stirred at 90° C. for 18 h, thencooled to RT and diluted with EtOAc (60 mL). The insoluble solid wasfiltered off and the clear filtrate was concentrated under reducedpressure. The crude product was purified preparative TLC using 3% MeOHin DCM as a mobile phase to afford 52 mg (15%) ofCIS—N-(2-cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide(SC_5022) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.56).[M+H]⁺532.3

Synthesis of SC_5031:CIS-3-[8-dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide

50% Propylphosphonic anhydride (T3P) solution in ethyl acetate (0.766mL, 1.204 mmol) was added to a solution of crudeCIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicacid trifluoroacetate (INT-896) (100 mg, 0.193 mmol), 2-aminoethanol(0.035 mL, 0.580 mmol) and diisopropylethylamine (0.167 mL, 0.966 mmol)in DCM (4 mL) at 0° C. The reaction mixture was warmed to RT and stirredfor 4 h and then quenched with water. The organic product was extractedwith DCM (3×20 mL). The combined organic layer was washed with sat. aq.NaHCO₃ (10 mL), brine (10 mL), dried over anhydr. Na₂SO₄ andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give 31 mg ofCIS-3-[8-dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)propionamide(SC_5031) as an off-white solid. [M+H]⁺ 447.3

Synthesis of SC_5034:CIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide

30% aq. H₂O₂ (0.2 mL, 0.74 mmol) was added to a suspension ofCIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethylpropionitrile(INT-793) (80 mg, 0.187 mmol) and K₂CO₃ (52 mg, 0.37 mmol) in DMSO at10-15° C. The resulting reaction mixture was warmed to RT and stirredfor 18 h. The reaction mixture was quenched with water and the organicproduct was extracted with EtOAc (3×10 mL). The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The resulting crude product was purified bypreparative TLC (2% MeOH in DCM) to yield 30 mg ofCIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide(SC_5034) (25%) as an off-white solid. (TLC system: 10% MeOH in DCMR_(f): 0.40). [M+H]⁺ 445.3

Synthesis of SC_5055:CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide

50% Propylphosphonic anhydride (T3P) solution in DMF (1.1 mL, 1.748mmol) was added to a mixture of crudeCIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionicacid (INT-899) (300 mg, 0.699 mmol, crude, contaminated with4-methylbenzene-sulfonic acid), oxetan-3-amine hydrochloride (91 mg,0.839 mmol) and diisopropylethylamine (0.51 mL, 2.797 mmol) in DMF (6mL) at 0° C. The reaction mixture was warmed to RT and stirred for 6 h,then quenched with water and the organic product was extracted withEtOAc (3×20 mL). The combined organic layer was washed with sat. aq.NaHCO₃ (10 mL), brine (10 mL), dried over anhydr. Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bypreparative TLC by using 3% methanol in DCM as a mobile phase to yield140 mg (41%) ofCIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide(SC_5055) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.55).[M+H]⁺ 485.3

Synthesis of SC_5056:CIS—N-(carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide

50% propylphosphonic anhydride (T3P) solution in DMF (3.99 mL, 6.27mmol) was added to a solution ofCIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionicacid (INT-897) (1.2 g, 2.51 mmol), 2-aminoacetamide hydrochloride (0.41g, 3.76 mmol) and diisopropylethylamine (2.63 mL, 15.06 mmol) in DMF (15mL) at 0° C. The reaction mixture was warmed to RT and stirred for 16 h.The reaction mixture was quenched with water, the organic product wasextracted with DCM (3×15 mL). The combined organic extracts were washedwith brine, dried over anhydr. Na₂SO₄ and concentrated under reducedpressure. The resulting crude product was purified by reverse phasepreparative HPLC to give 105 mg ofCIS—N-(carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide(SC_5056) as an off-white solid. (TLC system: 10% MeOH in DCM R_(f):0.4). [M+H]⁺ 442.3

Synthesis of SC_5059:CIS-3-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide

N-Iodosuccinimide (104.6 mg, 0.465 mmol) was added to a solution ofCIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide(SC_5055) (150 mg, 0.309 mmol) in a mixture of acetonitrile and THF (1:1v/v, 8 mL) at 0° C. and the resulting mixture was stirred for 16 h atRT. The reaction mixture was basified with 2N aq. NaOH to pH-10 and theorganic product was extracted with EtOAc (3×30 mL). The combined organicextracts were dried over anhydr. Na₂SO₄ and concentrated in vacuo. Theresulting crude product was purified by preparative reverse phase HPLCto give 70 mg of the desired product as a formic acid salt. The isolatedproduct was diluted with water (8 mL) and basified with solid NaHCO₃.The resulting mixture was extracted with ethyl acetate (2×30 mL), thecombined organic layer was dried over anhydr. Na₂SO₄ and concentrated invacuo to yield 60 mg (41%) ofCIS-3-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide(SC_5059) as an off-white solid (TLC system: 5% MeOH in DCM; R_(f):0.44.). [M+H]⁺ 471.3

Synthesis of SC_5063:CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanenitrile

Step 1:CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile

To a solution ofCIS-3-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-2,2-dimethyl-propionitrile(SC_5062) (1.8 g, 5.08 mmol, 1.0 eq.) in THF (20 ml) was added NaH (95%,366 mg, 15.25 mmol, 3.0 eq.) at 0° C. and the reaction mixture wasstirred for 20 min at RT. A solution of methoxymethyl chloride (0.57 ml,7.62 mmol, 1.5 eq.) in THF (5 ml) was added at 0° C. and the resultingmixture was stirred at RT for 16 h. The reaction mixture was dilutedwith water (20 ml) and extracted with EtOAc (2×50 ml). The combinedorganic layers were washed with water (50 ml) and brine (50 ml), driedover anhydr. Na₂SO₄ and concentrated under reduced pressure. Theresulting crude product was purified by column chromatography (neutralalumina; 0.2% MeOH/DCM) to yieldCIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(700 mg, 1.75 mmol, 34%) as an off-white sticky solid. LC-MS: m/z[M+H]⁺=399.3 (MW calc.=398.54).

Step 2:CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile

To a solution ofCIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(700 mg, 1.75 mmol, 1.0 eq.) in acetonitrile (20 ml) and THF (10 ml) wasadded N-iodosuccinimide (590 mg, 2.63 mmol, 1.5 eq.) at 0° C. and themixture was stirred at RT for 3 h. The reaction mixture was diluted withwater (20 ml) and 1N aq. NaOH (5 ml) and extracted with DCM (2×30 ml).The combined organic layers were washed with brine (40 ml), dried overanhydr. Na₂SO₄ and concentrated under reduced pressure to giveCIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(350 mg, 0.911 mmol, 52%) which was used directly for next step withoutfurther purification. LC-MS: m/z [M+H]+=385.2 (MW calc.=384.52).

Step 3:CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanenitrile(SC_5063)

To a solution ofCIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(400 mg, 1.04 mmol, 1.0 eq.) in MeOH (10 ml) was added 2M aq. HCl (30ml) at 0° C. and the mixture was stirred at RT for 16 h. The reactionmixture was basified with 2M aq. NaOH and extracted with DCM (2×25 ml).The combined organic layers were washed with brine (30 ml), dried overanhydr. Na₂SO₄ and concentrated under reduced pressure to giveCIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanenitrile(SC_5063) (300 mg, 0.882 mmol, 84%) which was 95.72% pure according toHPLC. LC-MS: m/z [M+H]+=341.27 (MW calc.=340.46). ¹HNMR (DMSO-d6, 400MHz), δ (ppm)=7.42-7.19 (m, 5H), 6.78 (bs, 1H), 3.36 (s, 2H), 3.18 (s,2H), 1.96-1.85 (m, 7H), 1.66 (bs, 2H), 1.46-1.43 (m, 2H), 1.25 (s, 6H).

Synthesis of SC_5074:CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutlnmethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide

Step 1:CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile

To a solution ofCIS-3-(8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(SC_5061) (250 mg, 0.679 mmol, 1.0 eq.) in DMSO (10 ml) was added NaOH(108 mg, 2.716 mmol, 4.0 eq.) at RT and the reaction mixture was stirredat 60° C. for 30 min. A solution of 1-oxa-spiro[2.3]hexane (142 mg, 1.69mmol, 2.5 eq.) in DMSO (1 ml) was added at RT. The reaction mixture wasstirred at 55° C. for 16 h, then diluted with water (100 ml) andextracted with ethyl acetate (60 ml). The organic layer was washed withwater (50 ml) and brine (50 ml), dried over anhydr. Na₂SO₄ andconcentrated under reduced pressure. The resulting crude product waspurified by column chromatography (neutral alumina; 30% ethylacetate/hexane) to yieldCIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(120 mg, 0.265 mmol, 39%) as an off-white solid. LC-MS: m/z [M+1]+=453.1(MW calc. 452.63).

Step 2:CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide(SC_5074)

In analogy to the method described for SC_5034CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrilewas treated with 30% aq. H₂O₂ in the presence of DMSO and potassiumcarbonate to be converted intoCIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide(SC_5074). Yield: 44% (55 mg, 0.117 mmol). LC-MS: m/z [M+H]+=471.1 (MWcalc.=470.65). ¹HNMR (DMSO-d6, 400 MHz), δ (ppm)=7.34-722 (m, 5H), 7.16(s, 1H), 6.95 (s, 1H), 6.11 (s, 1H), 3.25 (s, 2H), 3.16 (s, 2H), 3.09(s, 2H), 2.68-2.65 (m, 2H), 2.20-1.99 (m, 6H), 1.95-1.87 (m, 5H),1.63-1.61 (m, 1H), 1.43-1.23 (m, 6H), 1.02 (s, 6H), 0.99 (t, 3H, J=6.94Hz).

Synthesis of SC_5075:CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile

CIS—1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-984) (50 mg, 0.15 mmol) was added to a suspension of NaH (60% inmineral oil, 18 mg, 0.45 mmol) in DMF (5 mL) at 0° C. and the reactionmixture was stirred at RT for 5 min. 2-Cyano-2-methylpropyl4-methylbenzenesulfonate (113 mg, 0.45 mmol) was added at 0° C. andstirring was continued 120° C. for 16 h. The reaction mixture wasquenched with cold water and the organic product was extracted with DCM(3×20 mL). The combined organic extracts were dried over anhydr. Na₂SO₄and concentrated under reduced pressure. The above described reactionwas repeated with 300 mg of CIS—1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-984). Both reaction batches were combined and purified by columnchromatography (silica gel 100-200 mesh, 0-10% MeOH in DCM) to yield theproduct which was further purified by reverse phase preparative HPLC toafford 41 mg (16%) ofCIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile(SC_5075) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf:0.40). ¹H NMR (DMSO-d6): δ 7.37-7.23 (m, 5H), 3.38 (s, 2H), 3.22 (s,2H), 2.94 (d, 2H), 2.71-2.68 (m, 2H), 2.18 (t, 2H), 1.97 (s, 6H),1.42-1.30 (m, 4H), 1.26 (s, 6H), 0.93-0.92 (m, 1H), 0.48-0.44 (m, 2H),0.28-0.24 (m, 2H). [M+H]⁺ 471.3

Synthesis of SC_5079:CIS-8-(dimethylamino)-3-(3-(1,1-dioxidothiomorpholino)-2,2-dimethyl-3-oxopropyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-3-(2,2-dimethyl-3-oxo-3-thiomorpholinopropyl)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionicacid (INT-1075) (250 mg, 0.55 mmol, 1.0 eq) in DCM (20 mL) were addedDIPEA (0.29 mL, 1.65 mmol, 3.0 eq.), HATU (209 mg, 0.55 mmol, 1.0 eq.)and thiomorpholine (83 μL, 0.82 mmol, 1.5 eq.) at 0° C. The reactionmixture was stirred at RT for 16 h, diluted with DCM (100 mL), washedwith water (50 mL), sat. aq. NaHCO₃ (50 mL) and brine (50 mL). Organiclayer was dried over sodium sulfate and concentrated under reducedpressure to get crude product which was purified by columnchromatography (silica gel; 3% MeOH in DCM) to yieldCIS-8-dimethylamino-3-(2,2-dimethyl-3-oxo-3-thiomorpholin-4-yl-propyl)-1-(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(220 mg, 0.40 mmol, 73%) as an off-white solid. LC-MS: m/z [M+1]⁺=543.3(MW calc.=542.78).

Step 2:CIS-8-(dimethylamino)-3-(3-(1,1-dioxidothiomorpholino)-2,2-dimethyl-3-oxopropyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_5079)

To a solution ofCIS-8-dimethylamino-3-(2,2-dimethyl-3-oxo-3-thiomorpholin-4-yl-propyl)-1-(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(270 mg, 0.5 mmol, 1.0 eq) in acetone/THF/H₂O (40 mL, 6/1/1 v/v/v) wasadded oxone (615 mg, 1.0 mmol, 2.0 eq.) at 0° C. The reaction mixturewas stirred at RT for 16 h, quenched with sat. aq. Na₂SO₃, diluted withEtOAc (150 mL) and washed with sat. aq. NaHCO₃ (75 mL). Organic layerwas dried over sodium sulfate and concentrated under reduced pressure toget crude product which was purified by column chromatography (silicagel; 4% MeOH in DCM) to yieldCIS-8-dimethylamino-3-[3-(1,1-dioxo-116-thiomorpholin-4-yl)-2,2-dimethyl-3-oxo-propyl]-1-(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC_5079) (100 mg, 0.17 mmol, 34%) as a white solid. ¹HNMR (DMSO-d₆, 400MHz), δ (ppm)=7.37-7.25 (m, 5H), 5.91 (s, 1H), 3.92 (bs, 4H), 3.28 (bs,4H), 3.13 (bs, 4H), 3.07 (s, 2H), 2.64 (d, 2H, J=13.44 Hz), 2.07-2.00(m, 4H), 1.96 (s, 6H), 1.87-1.85 (m, 2H), 1.61-1.64 (m, 1H), 1.40-1.30(m, 5H), 1.19 (s, 6H). LC-MS: m/z [M+]⁺=575.1 (MW calc.=574.78).

Synthesis of SC_5083:CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide

Step 1: sodiumCIS-3-(1-(cyclopropylmethyl)-8-(dimethylanmino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)propanoate

To a solution ofCIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1063) (100 mg, 0.29 mmol) in dry THF (2.4 mL) cooled to 0° C. wasadded potassium tert-butoxide (1.5 equiv., 0.43 mmol, 49 mg). Thereaction mixture was stired for 15 min at 0° C. and methyl3-bromopropionate (1.2 equiv., 0.35 mmol, 38 μL) was added dropwise. Thereaction mixture was stirred at RT for 16 h and new portions of methyl3-bromopropionate (1.2 equiv., 0.35 mmol, 38 μL) and potassiumtert-butoxide (1.5 equiv., 0.43 mmol, 49 mg) were added. The reactionmixture was stirred for 3 h at RT, quenched with sat. aq. NaHCO₃ andthen extracted with DCM (2×). To the combined organic phase 2 mL of 2Maq. NaOH were added, the resulting mixture was vigorously stirredovernight at RT and then concentrated under reduced pressure to yieldcrude sodiumCIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)propanoate(60 mg, 50%) which was used in the next step without furtherpurification. LC-MS: m/z [M+1]+=418.3 (MW calc. 417.3)

Step 2:CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide(SC_5083)

To a solution of sodiumCIS-3-[1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]propanoate(60 mg, 0.144 mmol, 60 mg) and N-methylmethanamine (8 equiv., 1.15 mmol,2 M in THF, 0.57 mL) in DCM (1 mL) was added propylphosphonic anhydridesolution ≥50 wt. % in EtOAc (2 equiv., 0.29 mmol, 0.17 mL). The reactionmixture was stirred at RT overnight, then quenched with sat. aq. NaHCO₃(2 mL) and diluted with EtOAc. The organic phase was separated and theaqueous phase extracted with EtOAc. The combined organic layers weredried over anhydr. Na₂SO₄ and concentrated under reduced pressure. Theresulting crude product was purified by flash chromatography (eluentgradient DCM/MeOH) to yieldCIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide(SC_5083) (25 mg, 39%). LC-MS: m/z [M+H]⁺=445.3 (MW calc.=444.29). ¹HNMR (600 MHz, DMSO) δ 7.40 (td, 1H), 7.21-7.05 (m, 3H), 3.27 (t, 2H),3.18 (s, 2H), 2.95 (s, 3H), 2.91 (d, 2H), 2.79 (s, 3H), 2.67-2.55 (m,2H), 2.47 (t, 2H), 2.13 (ddd, 2H), 1.99 (s, 6H), 1.43-1.21 (m, 4H), 0.92(ddt, 1H), 0.49-0.41 (m, 2H), 0.30-0.21 (m, 2H).

For further exemplary compounds the last synthesis step in analogy topreviously described methods is given in the following table. Thesyntheses of the building blocks and intermediates have either beendescribed previously within this application or can be performed inanalogy to the herein described methods or by methods known to theperson, skilled in the art. Such a person will also know which buildingblocks and intermediates need to be chosen for synthesis of eachexemplary compound.

in analogy m/z Example Chemical Name Reactant I Reactant II to method[M + H]⁺ SC_5001 CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899pyridazin-3- SC_5055 507.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- aminediazaspiro[4.5]decan-3-yl]-N-pyridazin-3- yl-propionamide SC_5002CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 NH₄Cl SC_5055 429.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5004CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 6- SC_5003 520.3dimethylamino-2-oxo-8-phenyl-1,3- methoxypyridin-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy- 3-aminepyridin-3-yl)-propionamide SC_5005 CIS-3-[1-(Cyclobutyl-methyl)-8- INT998 3- SC_5003 520.3 dimethylamino-2-oxo-8-phenyl-1,3- methoxypyridin-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy- 4-aminepyridin-4-yl)-propionamide SC_5006 CIS-3-[1-(Cyclobutyl-methyl)-8- INT998 6- SC_5003 521.3 dimethylamino-2-oxo-8-phenyl-1,3- methoxypyridazin-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy- 3-aminepyridazin-3-yl)-propionamide SC_5007 CIS-3-[1-(Cyclobutyl-methyl)-8- INT998 5- SC_5003 568.3 dimethylamino-2-oxo-8-phenyl-1,3- (methylsulfonyl)diazaspiro[4.5]decan-3-yl]-N-(5- pyridin-2-aminemethylsulfonyl-pyridin-2-yl)- propionamide SC_5008CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 5- SC_5003 520.3dimethylamino-2-oxo-8-phenyl-1,3- methoxypyridin-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy- 2-aminepyridin-2-yl)-propionamide SC_5009 CIS-3-[1-(Cyclobutyl-methyl)-8- INT998 6- SC_5003 568.3 dimethylamino-2-oxo-8-phenyl-1,3- (methylsulfonyl)diazaspiro[4.5]decan-3-yl]-N-(6- pyridin-3-aminemethylsulfonyl-pyridin-3-yl)-propionamide SC_5010CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 6- SC_5003 521.3dimethylamino-2-oxo-8-phenyl-1,3- methoxypyrazin-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy- 2-aminepyrazin-2-yl)-propionamide SC_5011 CIS-3-[1-(Cyclobutyl-methyl)-8- INT998 4- SC_5003 520.3 dimethylamino-2-oxo-8-phenyl-1,3- methoxypyridin-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy- 2-aminepyridin-2-yl)-propionamide SC_5012 CIS-3-[1-(Cyclobutyl-methyl)-8- INT998 oxazol-5- SC_5003 494.3 dimethylamino-2-oxo-8-phenyl-1,3-ylmethanamine diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-propionamide SC_5013 CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998oxazol-2- SC_5003 494.3 dimethylamino-2-oxo-8-phenyl-1,3- ylmethanaminediazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl- methyl)-propionamide SC_5014CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4- INT 998 piperidine-3,4- SC_5003513.3 dihydroxy-piperidin-1-yl]-3-oxo-propyl]- diol8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_5015CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4- INT 998 pyrrolidine-3,4- SC_5003499.3 dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]- diol8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_5016CIS-1-(Cyclobutyl-methyl)-3-[3-[(3S,4R)- INT 998 (3S,4R)- SC_5003 499.33,4-dihydroxy-pyrrolidin-1-yl]-3-oxo- pyrrolidine-3,4-propyl]-8-dimethylamino-8-phenyl-1,3- diol diazaspiro[4.5]decan-2-oneSC_5017 CIS-1-(Cyclobutyl-methyl)-8- INT 998 piperidin-3-ol SC_5003497.3 dimethylamino-3-[3-(3-hydroxy-piperidin-1-yl)-3-oxo-propyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_5018CIS-3-[1-(Cyclobutyl-methyl)-8- INT 998 1- SC_5003 497.3dimethylamino-2-oxo-8-phenyl-1,3- (aminomethyl)cyclobutanoldiazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-propionamide SC_5019 CIS-1-(Cyclobutyl-methyl)-8-INT 998 5,6,7,8- SC_5003 520.3 dimethylamino-3-[3-oxo-3-(5,6,7,8-tetrahydro- tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-[1,2,4]triazolo[1,5- yl)-propyl]-8-phenyl-1,3- a]pyrazinediazaspiro[4.5]decan-2-one SC_5020 CIS-3-[3-[1-(Cyclobutyl-methyl)-8-INT 998 3-amino-N,N- SC_5003 512.4 dimethylamino-2-oxo-8-phenyl-1,3-dimethylpropanamide diazaspiro[4.5]decan-3-yl]-propanoylamino]-N,N-dimethyl- propionamide SC_5023CIS-3-[8-Dimethylamino-1-[(1-hydroxy- SC_5002 2- SC_5022 507.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- bromopyrimidinediazaspiro[4.5]decan-3-yl]-N-pyrimidin-2- yl-propionamide SC_5024CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT-899 2- SC_5055 523.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- aminopyrimidin-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy- 4(3H)-onepyrimidin-2-yl)-propionamide SC_5025CIS-3-[8-Dimethylamino-1-[(1-hydroxy- SC_5002 2-bromo-4- SC_5022 537.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- methoxypyrimidinediazaspiro[4.5]decan-3-yl]-N-(4-methoxy- pyrimidin-2-yl)-propionamideSC_5026 CIS-3-[1-(Cyclobutyl-methyl)-8- SC_5046 — SC_5059 427.3methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5027 CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5054 — SC_5059459.3 methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2- hydroxy-ethyl)-propionamide SC_5028CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5002 — SC_5059 415.3methyl]-8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5029 CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5052 — SC_5059429.3 methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5030CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5001 — SC_5059 493.3methyl]-8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide SC_5032 CIS-3-[8-Dimethylamino-1-(2-methoxy-INT 896 methylamine SC_5031 417.3 ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5033CIS-3-[8-Dimethylamino-1-(2-methoxy- INT 896 pyrimidin-5- SC_5031 481.3ethyl)-2-oxo-8-phenyl-1,3- aminediazaspiro[4.5]decan-3-yl]-N-pyrimidin-5- yl-propionamide SC_5035CIS-3-[8-Dimethylamino-1-(2-methoxy- INT-792 — SC_5034 431.3ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5036 CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899pyridin-3-amine SC_5055 506.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl- propionamide SC_5037CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 pyridin-4-amine SC_5055506.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl- propionamide SC_5038CIS-2-[3-[8-Dimethylamino-1-(3- INT 896 2-amino-2- SC_5031 502.3methoxy-propyl)-2-oxo-8-phenyl-1,3- methylpropanamidediazaspiro[4.5]decan-3-yl]- propanoylamino]-2-methyl-propionamideSC_5039 CIS-3-[8-Dimethylamino-1-(3-methoxy- INT 896 2- SC_5031 523.3propyl)-2-oxo-8-phenyl-1,3- (methylsulfonyl)diazaspiro[4.5]decan-3-yl]-N-(2- ethanaminemethylsulfonyl-ethyl)-propionamide SC_5040CIS-3-[8-Dimethylamino-1-(3-methoxy- INT 896 2-aminoethanol SC_5031461.3 propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy- ethyl)-propionamide SC_5041CIS-8-Dimethylamino-1-(3-methoxy- INT 896 piperazin-2-one SC_5031 500.3propyl)-3-[3-oxo-3-(3-oxo-piperazin-1-yl)- propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_5042 CIS-(2R)-1-[3-[8-Dimethylamino-1-(3-INT 896 (R)-pyrrolidine- SC_5031 514.3methoxy-propyl)-2-oxo-8-phenyl-1,3- 2-carboxamidediazaspiro[4.5]decan-3-yl]-propanoyl]- pyrrolidine-2-carboxylic acidamide SC_5043 CIS-N-(Carbamoyl-methyl)-3-[8- INT 896 2- SC-5031 474.3dimethylamino-1-(3-methoxy-propyl)-2- aminoacetamideoxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl]-propionamide SC_5044CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 pyridin-2-amine SC_5055506.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl- propionamide SC_5045CIS-3-[1-(Cyclobutyl-methyl)-8-(ethyl- INT-791 — SC_5034 455.3methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl- propionamide SC_5046CIS-3-[1-(Cyclobutyl-methyl)-8- INT-897 — SC_5034 441.3dimethylamino-2-oxo-8-phenyl-1,3- productdiazaspiro[4.5]decan-3-yl]-2,2-dimethyl- step 1 propionamide SC_5047CIS-3-[1-(Cyclobutyl-methyl)-8- INT-898 NH₄Cl SC_5031 413.3dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5048CIS-3-[1-(Cyclobutyl-methyl)-8-[methyl- INT 894 methylamine SC_5031469.4 (2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5049CIS-3-[1-(Cyclobutyl-methyl)-8- INT 898 methylamine SC_5031 427.3dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5051 CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899pyrimidin-5- SC_5055 507.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- aminediazaspiro[4.5]decan-3-yl]-N-pyrimidin-5- yl-propionamide SC_5052CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 methylamine SC_5055 443.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl- propionamide SC_5053CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 2- SC_5055 487.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- methoxyethanaminediazaspiro[4.5]decan-3-yl]-N-(2-methoxy- ethyl)-propionamide SC_5054CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT 899 2-aminoethanol SC_5055473.3 cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy- ethyl)-propionamide SC_5057CIS-N-(Carbamoyl-methyl)-3-[1- SC_5056 — SC_5059 484.3(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl]-2,2-dimethyl-propionamideSC_5058 CIS-3-[8-Dimethylamino-1-[(1-hydroxy- INT-790 — SC_5034 457.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl- propionamide SC_5060CIS-3-[1-[(1-Hydroxy-cyclobutyl)- SC_5058 — SC_5059 443.3methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2- dimethyl-propionamide in analogy m/zExample Chemical name Reactant I Reactant II to method ¹H NMR data (M +H)⁺ SC_5061* CIS-3-[8-(Ethyl- INT-797 3-bromo-2,2- step 1 of 1HNMR(DMSO-d6, 369.2 methyl-amino)-2- dimethyl- INT-897 400 MHz, at 100 0C.), δ oxo-8-phenyl-1,3- propionitrile (ppm) = 7.34-7.21 (m,diazaspiro[4.5]decan- 5H), 6.70 (bs, 1H), 3.28 3-yl]-2,2-dimethyl- (s,2H), 3.19 (s, 2H), propionitrile 2.32-2.24 (m, 4H), 2.06 (s, 3H),1.87-1.82 (m, 4H), 1.45-1.37 (bs, 2H), 1.27 (s, 6H), 0.93 (t, 3H, 6.8Hz). SC_5062* CIS-3-(8- INT-976 3-bromo-2,2- step 1 of 1HNMR (DMSO-d6,355.2 Dimethylamino-2- dimethyl- INT-897 400 MHz), δ (ppm) =oxo-8-phenyl-1,3- propionitrile 7.35-7.24 (m, 5H), 7.03diazaspiro[4.5]decan- (bs, 1H), 3.25 (s, 2H), 3-yl)-2,2-dimethyl- 3.15(s, 2H), 2.32 (bs, propionitrile 2H), 1.92 (s, 6H), 1.82 (bs, 4H), 1.38(bs, 2H), 1.24 (s, 6H). SC_5064 CIS-3-[8-(Ethyl- SC_5061 SC_5034 1HNMR(DMSO-d6, 387.5 methyl-amino)-2- 400 MHz), δ (ppm) = oxo-8-phenyl-1,3-7.33-7.22 (m, 5H), 7.14 diazaspiro[4.5]decan- (bs, 1H), 6.83-6.79 (m,3-yl]-2,2-dimethyl- 2H), 3.07 (s, 2H), 3.01 propionamide (s, 2H), 2.32(bs, 2H), 2.11 (bs, 2H), 1.96 (s, 3H), 1.78-1.69 (m, 4H), 1.31 (bs, 2H),0.99 (s, 6H), 0.90 (t, 3H, J = 6.66 Hz). SC_5065* CIS-3-[8-(Ethyl-SC_5061 methyl iodide step 1 of 1HNMR (DMSO-d6, 383.2 methyl-amino)-1-INT-953 400 MHz), δ (ppm) = methyl-2-oxo-8- 7.34-722 (m, 5H), 3.38phenyl-1,3- (s, 2H), 3.21 (s, 2H), diazaspiro[4.5]decan- 2.71-2.64 (m,5H), 3-yl]-2,2-dimethyl- 2.19-2.16 (m, 4H), 1.96 propionitrile (s, 3H),1.37-1.30 (m, 4H), 1.25 (s, 6H), 0.98 (t, 3H, J = 6.48 Hz). SC_5066CIS-3-[8-(Ethyl- SC_5065 SC_5034 1HNMR (DMSO-d6, 401.2 methyl-amino)-1-400 MHz), δ (ppm) = methyl-2-oxo-8- 7.34-723 (m, 5H), 7.15 phenyl-1,3-(s, 1H), 6.90 (s, 1H), diazaspiro[4.5]decan- 3.13 (s, 4H), 2.67-2.603-yl]-2,2-dimethyl- (m, 5H), 2.12-2.09 (m, propionamide 4H), 1.95 (s,3H), 1.33-1.25 (m, 4H), 1.01-0.97 (m, 9H). SC_5067 CIS-2,2-Dimethyl-3-SC_5063 SC_5034 1HNMR (DMSO-d6, 358.48 (8-methylamino-2- 400 MHz), δ(ppm) = oxo-8-phenyl-1,3- 7.42 (d, 2H, J = 8), diazaspiro[4.5]decan-7.33-7.29 (t, 2H, J = 8), 3-yl)-propionamide 7.19-7.15 (m, 2H), 6.90 (s,1H), 6.51 (bs, 1H), 3.12-3.09 (m, 4H), 1.90-1.83 (m, 7H), 1.74-1.69 (m,2H), 1.41-1.38 (d, 2H, J = 12), 1.01 (s, 6H) SC_5068* CIS-3-(8- INT-10083-bromo-2,2- step 1 of 1HNMR (DMSO-d6, 355.1 Ethylamino-2-oxo-8-dimethyl- INT-897 400 MHz), δ (ppm) = phenyl-1,3- propionitrile 7.42 (d,12H, J = 7.32 diazaspiro[4.5]decan- Hz), 7.30 (t, 2H, J =3-yl)-2,2-dimethyl- 7.20 Hz), 7.17 (t, 1H, J = propionitrile 7.12 Hz),6.78 (s, 1H), 3.35 (s, 2H), 3.17 (s, 2H), 2.05 (m, 7H), 1.67-1.43 (m,4H), 1.25 (s, 6H), 0.91 (t, 3H, J = 6.78 Hz). SC_5069 CIS-3-(8- SC_5068SC_5034 1HNMR (DMSO-d6, 373.0 Ethylamino-2-oxo-8- 400 MHz, at 100 0 C.),δ phenyl-1,3- (ppm) = 7.45 (d, 2H, J = diazaspiro[4.5]decan- 6.52 Hz),7.32 (t, 2H, 3-yl)-2,2-dimethyl- J = 7.2 Hz), 7.21 (t, 1H, propionamideJ = 6.66 Hz), 6.64 (bs, 2H), 6.18 (s, 1H), 3.16 (s, 4H), 2.19 (bs, 2H),1.91-1.79 (m, 6H), 1.44 (bs, 2H), 1.07 (s, 6H), 0.95 (t, 3H, J = 6.62Hz). SC_5070 CIS-3-(8- SC_5062 SC_5034 1H NMR (600 MHz, 373.3Dimethylamino-2- DMSO) δ 7.39-7.29 oxo-8-phenyl-1,3- (m, 4H), 7.29-7.22diazaspiro[4.5]decan- (m, 1H), 7.14 (s, 1H), 3-yl)-2,2-dimethyl- 6.81(s, 1H), 6.76 (s, propionamide 1H), 3.09 (s, 2H), 3.03 (s, 2H),2.40-2.21 (m, 2H), 1.93 (s, 6H), 1.82-1.74 (m, 2H), 1.74-1.61 (m, 2H),1.37-1.29 (m, 2H), 1.01 (s, 6H). SC_5071 CIS-3-[1- SC_5068 cyclobutyl-step 1 of 1HNMR (DMSO-d6, 441.0 (Cyclobutyl- methylbromide INT-953 (for400 MHz), δ (ppm) = methyl)-8- step 1), 7.42 (d, 2H, J = 7.48ethylamino-2-oxo-8- SC_5034 (for Hz), 7.30 (t, 2H, J = phenyl-1,3- step2) 7.32 Hz), 7.19-7.14 (m, diazaspiro[4.5]decan- 2H), 6.94 (s, 1H), 3.123-yl]-2,2-dimethyl- (s, 4H), 3.05 (d, 2H, J = propionamide 7.08 Hz),2.14-2.03 (m, 4H), 1.95-1.88 (m, 4H), 1.79-1.66 (m, 4H), 1.53-1.25 (m,4H), 1.01 (s, 6H), 0.95 (t, 3H). SC_5072 CIS-3-[8- SC_5062 toluene-4-step 1 of 1HNMR (DMSO-d6, 443.3 Dimethylamino-1- sulfonic acid INT-953(for 400 MHz), δ (ppm) = (oxetan-3-yl- oxetan-3- step 1), 7.37-7.24 (m,5H), 7.14 methyl)-2-oxo-8- ylmethyl ester SC_5034 (for (s, 1H), 6.92 (s,1H), phenyl-1,3- step 2) 4.62-4.58 (m, 2H), 4.35 diazaspiro[4.5]decan-(t, 2H, J = 6.02 Hz), 3-yl]-2,2-dimethyl- 3.29 (d, 2H, J = 7.28propionamide Hz), 3.14-3.08 (m, 5H), 2.68-2.65 (m, 2H), 2.01-1.95 (m,8H), 1.33-1.22 (m, 4H), 1.00 (s, 6H). SC_5073 CIS-3-[1- SC_5075 SC_50341HNMR (DMSO-d6, 427.4 (Cyclopropyl- 400 MHz), δ (ppm) = methyl)-8-7.35-7.25 (m, 5H), 7.15 dimethylamino-2- (s, 1H), 6.90 (s, 1H),oxo-8-phenyl-1,3- 3.13 (s, 4H), 2.90 (d, diazaspiro[4.5]decan- 2H, J =6.32 Hz), 2.68-2.65 3-yl]-2,2-dimethyl- (m, 2H), 2.15-2.09 propionamide(m 2H), 1.98 (s, 6H), 1.36-1.23 (m, 4H), 1.01(s, 6H), 0.91 (m, 1H), 0.44(d, 2H, J = 6.84 Hz), 0.24 (d, 2H, J = 4.08 Hz). SC_5076 CIS-8- INT-1075morpholine SC_5031 527.5 Dimethylamino-3- (2,2-dimethyl-3-morpholin-4-yl-3- oxo-propyl)-1-[(1- hydroxy- cyclobutyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan- 2-one SC_5077 CIS-3-[8- INT-1075 2-SC_5031 1HNMR (DMSO-d6, 501.2 Dimethylamino-1- aminoethanol 400 MHz at100 0 C.), δ [(1-hydroxy- (ppm) = 7.33-7.18 (m, cyclobutyl)-methyl]-6H), 5.66 (bs, 1H), 4.19 2-oxo-8-phenyl-1,3- (bs, 1H), 3.40 (bs, 2H),diazaspiro[4.5]decan- 3.25-3.22 (m, 4H), 3.13 3-yl]-N-(2-hydroxy- (bs,4H), 2.62-2.59 (m, ethyl)-2,2-dimethyl- 2H), 2.10-2.05 (m, 9H),propionamide 1.91-1.89 (m, 2H), 1.70-1.66 (m, 2H), 1.41-1.28 (m, 4H),1.09 (s, 6H). SC_5078 CIS-3-[l-[(1-Cyano- SC_5062 toluene-4- step 1 of¹HNMR (DMSO-d₆, 466.2 cyclobutyl)-methyl]- sulfonic acid INT-953 (for400 MHz), δ (ppm) = 8-dimethylamino-2- 1-cyano- step 1), 7.37-7.31 (m,4H), oxo-8-phenyl-1,3- cyclobutylmethyl SC_5034 (for 7.27-7.23 (m, 1H),diazaspiro[4.5]decan- ester step 2) 7.14 (s, 1H), 6.933-yl]-2,2-dimethyl- (s, 1H), 3.32 (s, 2H), propionamide 3.17 (s, 4 H),2.69-2.65 (d, 2H), 2.45-2.38 (m, 2H), 2.35-2.28 (m, 2H), 2.0-1.95 (m,10H), 1.41-1.38 (d, 2H), 1.30-1.23 (t, 2H), 1.02 (s, 6H). SC_5080*TRANS-3-[1- INT-1059 3-bromo-2,2- step 1 of 1HNMR at 20o C. 409.2(Cyclopropyl- dimethyl- INT-897 (for (DMSO-d6, 400 MHz), methyl)-8-propionitrile step 1), step δ (ppm) = 7.44-7.28 dimethylamino-2- (step1), 1 of INT-953 (m, 5H), 3.46 (s, 2H), oxo-8-phenyl-1,3- cyclopropyl-(for step 2) 3.23 (s, 2H), 2.72-2.66 diazaspiro[4.5]decan- methylbromide(m, 2H), 2.57-2.55 (m, 3-yl]-2,2-dimethyl- (step 2) 2H), 1.91 (s, 6H),1.55-1.45 propionitrile (m, 6H), 1.27 (s, 6H), 0.51 (bs, 1H), 0.19-0.14(m, 2H), (−0.22)-(−0.26) (m, 2H). SC_5081 TRANS-3-[8- INT-10593-bromo-2,2- step 1 of 1HNMR (DMSO-d6, 457.2 Dimethylamino-1- dimethyl-INT-897 (for 400 MHz), δ (ppm) = [(1-hydroxy- propionitrile step 1),7.43-7.27 (m, 5H), 7.21 cyclobutyl)-methyl]- (step 1), 1- SC_5074 (for(bs, 1H), 7.05 (bs, 1H), 2-oxo-8-phenyl-1,3- oxaspiro[2.3]hexane steps 2and 5.75 (s, 1H), 3.17 (s, diazaspiro[4.5]decan- (step 2) 3) 2H),2.67-2.65 (bs, 3-yl]-2,2-dimethyl- 2H), 2.55 (s, 2H), 1.91 propionamide(s, 6H), 1.73-1.68 (m, 4H), 1.48-1.34 (m, 7H), 1.04 (s, 6H), 0.90-0.83(m, 1H). SC_5082 TRANS-3-(8- INT-1061 3-bromo-2,2- step 1 of 1HNMR at100o C. 373.3 Dimethylamino-2- dimethyl- INT-897 (for (DMSO-d6, 400MHz), oxo-8-phenyl-1,3- propionitrile step 1), δ (ppm) = 7.37-7.25diazaspiro[4.5]decan- (step 1) SC_5034 (for (m, 5H), 6.68 (bs, 2H),3-yl)-2,2-dimethyl- step 2) 6.30 (bs, 1H), 3.22 (s, propionamide 2H),3.17 (s, 2H), 2.16 (bs, 2H), 1.99 (bs, 8H), 1.70-1.68 (m, 2H), 1.43-1.38(m, 2H), 1.09 (s, 6H). SC_5084 CIS-3-[1- INT-1031 2-cyano-2- SC_5075 1HNMR (DMSO-d6): 445.3 (Cyclopropyl- methylpropyl (step 1), δ 7.41-7.36(m, 1H), methyl)-8- 4- SC_5034 7.18-7.07 (m, 4H), 6.89dimethylamino-8-(3- methyl- (step 2) (br, s, 1H), 3.14 (s,fluorophenyl)-2-oxo- benzenesulfonate 4H), 2.90 (d, 2H), 2.64 1,3-(step 1) (d, 2H), 2.11 (t, 2H), diazaspiro[4.5]decan- 1.98 (s, 6H), 1.34(d, 3-yl]-2,2-dimethyl- 2H), 1.27 (t, 2H), 1.02 propionamide (s, 6H),0.93-0.88 (m, 1H), 0.47-0.42 (m, 2H), 0.26-0.22 (m, 2H). SC_5085CIS-1-((1- INT-983 (1- step 1 of 425.3 (cyclopropylmethyl)-cyanocyclopropyl)methyl INT-897 (for 8-(dimethylamino)- 4-methylbenzene-step 1), 2-oxo-8-phenyl-1,3- sulfonate SC_5034 (fordiazaspiro[4.5]decan- (step 1) step 2) 3-yl)methyl)cyclopropane-carboxamide SC_5086 CIS-3-((1- INT-983 (3- step 1 of 441.3(cyclopropylmethyl)- cyanooxetan- INT-897 (for 8-(dimethylamino)-3-yl)methyl 4- step 1), 2-oxo-8-phenyl-1,3- methylbenzene- SC_5034 (fordiazaspiro[4.5]decan- sulfonate step 2) 3-yl)methyl)oxetane-3- (step 1)carboxamide SC_5087 CIS-3-(1- SC_5073 step 2 of 413.3(cyclopropylmethyl)- SC_5063 8-(methylamino)-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan- 3-yl)-2,2- dimethylpropanamide SC_5088 CIS-3-(1-INT-983 3- step 1 of (cyclopropylmethyl)- bromopropane INT-897 (for8-(dimethylamino)- nitrile step 1), 2-oxo-8-phenyl-1,3- SC_5034 (fordiazaspiro[4.5]decan- step 2) 3-yl)propanamide SC_5089 CIS-3-(8- INT-9763-bromo-2,2- step 1 of (dimethylamino)-1- dimethyl- INT-897 (for((1-fluorocyclopropyl)methyl)- propionitrile step 1), step 2-oxo-8-(step 1), (1- 1 of INT-953 phenyl-1,3- fluorocyclopro- (for step 2),diazaspiro[4.5]decan- pyl)methyl 4- SC_5034 (for 3-yl)-2,2-methylbenzene- step 3) dimethylpropanamide sulfonate (step 2), H2O2nitrile hydrolysis (step 3) *comparative examples

The chemical structures of the example compounds are shown in thefollowing table.

SC_5001

SC_5022

SC_5042

SC_5002

SC_5023

SC_5043

SC_5003

SC_5024

SC_5044

SC_5004

SC_5025

SC_5045

SC_5005

SC_5026

SC_5046

SC_5006

SC_5027

SC_5047

SC_5007

SC_5028

SC_5048

SC_5008

SC_5029

SC_5049

SC_5009

SC_5030

SC_5051

SC_5010

SC_5031

SC_5052

SC_5011

SC_5032

SC_5053

SC_5012

SC_5033

SC_5054

SC_5013

SC_5034

SC_5055

SC_5014

SC_5035

SC_5056

SC_5015

SC_5036

SC_5057

SC_5016

SC_5037

SC_5058

SC_5017

SC_5038

SC_5059

SC_5018

SC_5039

SC_5060

SC_5019

SC_5040

SC_5020

SC_5041

SC_5061*

SC_5062*

SC_5063*

SC_5064

SC_5065*

SC_5066

SC_5067

SC_5068*

SC_5069

SC_5070

SC_5071

SC_5072

SC_5073

SC_5074

SC_5075*

SC_5076

SC_5077

SC_5078

SC_5079

SC_5080*

SC_5081

SC_5082

SC_5083

SC_5084

SC_5085

SC_5086

SC_5087

SC_5088

SC_5089 (*comparative examples)

Pharmacological Investigations

Functional investigation on the human mu-opioid receptor (hMOP), humankappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), andhuman nociceptin/orphanin FQ peptide receptor (hNOP)

Human Mu-Opioidpeptide (hMOP) Receptor Binding Assay

The hMOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin(Sigma-Aldrich Co. St. Louis. Mo.). The final assay volume (250 μl/well)included 1 nM of [N-allyl-2.3-³H]naloxone as ligand (PerkinElmer LifeSciences. Inc. Boston. Mass. USA). and either test compound in dilutionseries or 25 μM unlabelled naloxone for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration. which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston. Mass. USA). After incubation for 90 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]naloxone-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

Human Kappa-Opioidpeptide (hKOP) Receptor Binding Assay

The hKOP receptor binding assay is run as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of250 μl per well includes 2 nM of [³H]U69,593 as ligand, and either testcompound in dilution series or 100 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hKOP receptor membranes (14.8 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 90 minutes at room temperature. After this incubation, themicrotiter plates are sealed with a topseal and centrifuged for 20minutes at 500 rpm. The signal rate is measured after a short delay of 5minutes by means of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]U69.593-specificreceptor binding are calculated by nonlinear regression analysis andK_(i) values are calculated by using the Cheng-Prusoff equation, (Chengand Prusoff, 1973).

Human Delta-Opioidpeptide (hDOP) Receptor Binding Assay

The hDOP receptor binding assay is performed as homogeneous SPA-assayusing the assay buffer 50 mM TRIS-HCl, 5 mM MgCl₂ (pH 7.4). The finalassay volume (250 μl/well) includes 1 nM of[Tyrosyl-3,5-³H]2-D-Ala-deltorphin II as ligand, and either testcompound in dilution series or 10 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hDOP receptor membranes (15.2 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 120 minutes at room temperature and centrifuged for 20minutes at 500 rpm. The signal rate is measured by means of a 1450Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac, Turku,Finland). Half-maximal inhibitory concentration (IC50) values reflecting50% displacement of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II-specificreceptor binding are calculated by nonlinear regression analysis andK_(i) values are calculated by using the Cheng-Prusoff equation, (Chengand Prusoff, 1973).

Human Nociceptin/Orphanin FQpeptide (hNOP) Receptor Binding Assay

The hNOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl.10 mM MgCl₂. 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well)included 0.5 nM of [leucyl-³H]nociceptin as ligand (PerkinElmer LifeSciences. Inc. Boston. Mass. USA). and either test compound in dilutionseries or 1 μM unlabelled nociceptin for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration. which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston. Mass. USA). After incubation for 60 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]nociceptin-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

hNOP hMOP Example Ki [nM] Ki [nM] SC_5001 4 410 SC_5002 12.2 118 SC_50032.6 44.5 SC_5004 1.1 10 SC_5005 1.2 46.5 SC_5006 1.9 24.5 SC_5007 2.1 66SC_5008 1 25 SC_5009 1.8 43.5 SC_5010 2.2 19 SC_5011 2.6 51.5 SC_50125.8 28 SC_5013 3.6 8.2 SC_5014 6.6 33 SC_5015 10.6 24.5 SC_5016 11.4 31SC_5017 2.6 7.6 SC_5018 3.2 1.7 SC_5019 3 49 SC_5020 8.1 47.5 SC_50223.1 99.5 SC_5023 14.5 245 SC_5024 9.4 160 SC_5025 22.5 130 SC_5026 17.5555 SC_5027 215 1195 SC_5028 140 895 SC_5029 205 1635 SC_5030 20 810SC_5031 195 510 SC_5032 220 1130 SC_5033 48.5 1030 SC_5034 130 1185SC_5035 230 815 SC_5036 4.2 140 SC_5037 8 40 SC_5038 72.5 175 SC_5039130.5 130 SC_5040 115.5 395 SC_5041 63.5 445 SC_5042 70.5 190 SC_5043101 210 SC_5044 5.6 160.5 SC_5045 19 910 SC_5046 1 113.4 SC_5047 5.8 69SC_5048 1195 4146.7 SC_5049 1.5 11.3 SC_5051 3.6 320 SC_5052 12 250SC_5053 16.5 58.5 SC_5054 18.5 160 SC_5055 11.5 74 SC_5056 7.4 64SC_5057 75.5 124 SC_5058 19.5 545 SC_5059 111.5 88.5 SC_5060 285 1300SC_5064 3% @1 μM 3% @1 μM (DOP 20%) SC_5066 0% @1 μM 7% @1 μM (DOP 22%)SC_5067 1300 11% @1 μM SC_5069 1% @1 μM 7% @1 μM (KOP 50%) SC_5070 2457340 SC_5071 625 2845 SC_5072 150 4675 SC_5073 23 480 SC_5074 260 2615SC_5076 7 670 SC_5077 15 485 SC_5078 0.5 180 SC_5079 12 510 SC_5081 8154025 SC_5082 340 790 SC_5083 22 610 SC_5084 12 2475

Protocol for [³⁵S]GTPγS Functional NOP/MOP/KOP/DOP Assays

Cell membrane preparations of CHO— K1 cells transfected with the humanMOP receptor (Art.—No. RBHOMM) or the human DOP receptor (Art.—No.RBHODM), and HEK293 cells transfected with the human NOP receptor(Art.—No. RBHORLM) or the human KOP receptor (Art.—No. 6110558) areavailable from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cellstransfected with the human nociceptin/orphanin FQ peptide (hNOP)receptor (Art.—No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.)are also used. [³⁵S]GTPγS (Art.—No. NEG030H; Lot-No. #0112, #0913, #1113calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham,Mass.).

The [³⁵S]GTPγS assays are carried out essentially as described by Gillenet al (2000). They are run as homogeneous scintillation proximity (SPA)assays in microtiter luminescence plates, where each well contains 1.5mg of WGA-coated SPA-beads. To test the agonistic activity of testcompounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressingcell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane proteinper assay are incubated with 0.4 nM [³⁵S]GTPγS and serial concentrationsof receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4,100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN₃,and 10 μM GDP for 45 min at room temperature. The microtiter plates arethen centrifuged for 10 min at 830 to sediment the SPA beads. Themicrotiter plates are sealed and the bound radioactivity [cpm] isdetermined after a delay of 15 min by means of a 1450 Microbeta Trilux(PerkinElmer, Waltham, Mass.).

The unstimulated basal binding activity (UBS_(obs) [cpm]) is determinedfrom 12 unstimulated incubates and is set as 100% basal binding. Fordetermination of the potency and the efficacy, the arithmetic mean ofthe observed total [³⁵S]GTPγS binding (TB_(obs) [cpm]) of all incubates(duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ,SNC80, DAMGO, or U69,593) are transformed in percent total binding(TB_(obs) [%]) relative to the basal binding activity (i.e. 100%binding). The potency (EC₅₀) of the respective agonist and its maximalachievable total [³⁵S]GTPγS binding (TB_(calc) [%]) above its calculatedbasal binding (UBS_(cale) [%]) are determined from its transformed data(TB_(obs) [%]) by means of nonlinear regression analysis with XLfit foreach individual concentration series. Then the difference between thecalculated unstimulated [³⁵S]GTPγS binding (UBS_(calc) [%]) and themaximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) by eachtested agonist is determined (i.e. B1_(calc) [%]). This difference(B1_(calc) [%]) as a measure of the maximal achievable enhancement of[³⁵S]GTPγS binding by a given agonist is used to calculate the relativeefficacy of test compounds versus the maximal achievable enhancement bya receptor-specific full agonist, e.g. N/OFQ (B1_(calc-N/OFQ) [%]) whichis set as 100% relative efficacy for the hNOP receptor. Likewise, thepercentage efficacies of test compounds at the hDOP, hMOP, or hKOPreceptor are determined versus the calculated maximal enhancement of[³⁵S]GTPγS binding by the full agonists SNC80 (B1_(calc-SNC80) [%]),DAMGO (B1_(calc-DAMGO) [%]) and U69,593 (B1_(calc-U69,593) [%]) whichare set as 100% relative efficacy at each receptor, respectively.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A compound according to general formula (I)

wherein R¹ and R² independently of one another mean —H; —C₁-C₆-alkyl,linear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —OH,—OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered heterocycloalkyl moiety is optionally connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or R¹ and R² together with the nitrogen atom to whichthey are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 6-14-membered aryl moiety is optionallyconnected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; X means —O—, —S—or —NR⁶—; R⁵ means —H; —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; a 3-12-memberedcycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; incase X means NR⁶, R⁶ means —H; —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; or incase X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or R⁷ and R⁸ together with thecarbon atom to which they are attached form a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 3-12-membered heterocycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted; wherein “mono-or polysubstituted” means that one or more hydrogen atoms are replacedby a substituent independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹, —C(═O)OR²¹,—C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR²¹,—OC(═O)R²¹, —OC(═O)OR²¹, —OC(═O)NR²¹R²², —NO₂, —NR²¹R²²,—NR²¹—(CH₂)₁₋₆—C(═O)R²², —NR²¹—(CH₂)₁₋₆—C(═O)OR²²,—NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²², —NR²¹C(═O)—OR²²,—NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹, —S(═O)₂R²¹,—S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²; wherein R²¹, R²² and R²³ independentlyof one another mean —H; —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, and —O—C₁-C₆-alkyl; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; a 3-12-membered heterocycloalkyl moiety, saturatedor unsaturated, unsubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²²,—NR²¹R²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², Or—S(═O)₂NR²¹R²² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; or aphysiologically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R⁷ and R⁸ independently of one another mean —H or—C₁-C₆-alkyl.
 3. The compound according to claim 1, wherein R⁷ and R⁸together with the carbon atom to which they are attached form a ringselected from the group consisting of cyclopropyl, cyclobutyl orcyclopentyl, oxetanly, tetrahydrofuranyl or tetrahydropyranyl, in eachcase unsubstituted.
 4. The compound according to claim 1, wherein R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independentlyof one another mean —H, —F, —OH, or —C₁-C₆-alkyl.
 5. The compoundaccording to claim 1, wherein R¹ means —H; and R² means —C₁-C₆-alkyl,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 6. The compound according to claim 1, wherein R¹ means—CH₃; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 7. The compoundaccording to claim 1, wherein R¹ means —H or —CH₃; and wherein R² means—CH₂-cycloalkyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-oxetanyl or—CH₂-tetrahydrofuranyl.
 8. The compound according to claim 1, wherein R¹and R² together with the nitrogen atom to which they are attached form aring and mean —(CH₂)₃₋₆—.
 9. The compound according to claim 1, whereinR³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 10. The compound according toclaim 1, wherein R³ means a 6-14-membered aryl moiety, unsubstituted,mono- or polysubstituted.
 11. The compound according to claim 1, whereinR³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted.
 12. The compound according to claim 1, wherein R⁴ means—H.
 13. The compound according to claim 1, wherein R⁴ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 14. The compound according toclaim 1, wherein R⁴ means a 3-12-membered cycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 15. The compound according to claim 1, wherein R⁴ meansa 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 16. The compound according to claim 1, wherein R⁴ meansa 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 17. The compound according toclaim 1, wherein R⁴ means a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted; wherein said 5-14-memberedheteroaryl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 18. The compound according to claim 1, wherein R⁵ means—H.
 19. The compound according to claim 1, wherein R⁵ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 20. The compound according toclaim 1, wherein R⁵ means a 3-12-membered cycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted, wherein said3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 21. The compound according toclaim 1, wherein R⁵ means a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;wherein said 3-12-membered heterocycloalkyl moiety is optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 22. The compoundaccording to claim 1, wherein R⁵ means a 5-14-membered heteroarylmoiety, unsubstituted, mono- or polysubstituted; wherein said5-14-membered heteroaryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 23. The compound according toclaim 1, wherein X means NR⁶ and R⁵ and R⁶ together with the nitrogenatom to which they are attached form a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 24. The compound according to claim 1, wherein X meansNR⁶ and R⁶ means —H or —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 25. The compoundaccording to claim 1, which has a structure according to any of generalformulas (II-A) to (VIII-C):

wherein in each case R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and X are definedas in claim 1, R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; R^(D) means—H or —F; or a physiologically acceptable salt thereof.
 26. The compoundaccording to claim 1, wherein the substructure

has a meaning selected from the group consisting of:


27. The compound according to claim 1, wherein R¹ means —H or —CH₃; R²means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted; R³means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —CN, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃,—C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, —SOCH₃ and—SO₂CH₃; R⁴ means —H; —C₁-C₆-alkyl, linear or branched, saturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl; 3-6-membered cycloalkyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-memberedcycloalkyl is connected through —C₁-C₆-alkylene; or 3-6-memberedheterocycloalkyl, unsubstituted or substituted with one, two, three orfour substituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, whereinsaid 3-6-membered heterocycloalkyl is connected through —C₁-C₆-alkylene;X means —O— or —NR⁶-; R⁵ means —H; —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —OH, —S(═O)C₁-C₄-alkyl and —S(═O)₂ C₁-C₄-alkyl;cyclobutyl, unsubstituted or monosubstituted with —OH; wherein said-cyclobutyl is connected through —CH₂—; heterocyclobutyl, unsubstituted;or oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, Br, —I, —OH, —O—C₁-C₄-alkyl, —CN, and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionallyconnected through —CH₂—; in case X means NR⁶, R⁶ means —H or —CH₃; or incase X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form a piperidine moiety, a pyrrolidine moiety, amorpholine moiety, a thiomorpholine moiety, a thiomorpholine dioxidemoiety, or a piperazine moiety, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of ═O, —OH, and—C(═O)NH₂; wherein said piperidine moiety, pyrrolidine moiety,morpholine moiety, thiomorpholine moiety, thiomorpholine dioxide moiety,or piperazine moiety is optionally condensed with an imidazole moiety,unsubstituted; R⁷ and R⁸ independently of one another mean —H or —CH₃;or R⁷ and R⁸ together with the carbon atom to which they are attachedform a ring selected from the group consisting of cyclopropyl,cyclobutyl, heterocyclobutyl and heterocyclohexyl, in each caseunsubstituted; and R⁹, R¹⁰, R¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,and R²⁰ mean —H.
 28. The compound according to claim 1, which has astructure according to general formula (I′)

wherein R¹ to R⁵, R⁷ to R²⁰, and X are defined as in claim 1, or aphysiologically acceptable salt thereof.
 29. The compound according toclaim 1, which has a structure according to general formula (IX)

wherein R^(C) means —H or —OH; R^(D) means —H or —F; R⁵ means —H, —CH₃,or —CH₂CH₂—OH; R⁶ means —H or —CH₃; and R⁷ means —CH₃ and R⁸ means —CH₃;or R⁷ and R⁸ together with the carbon atom to which they are attachedform a cyclopropyl ring; or a physiologically acceptable salt thereof.30. The compound according to claim 1, which is selected from the groupconsisting ofCIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-propionamide;CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-piperidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-3-[3-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-(3-hydroxy-piperidin-1-yl)-3-oxo-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-propionamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-oxo-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-N,N-dimethyl-propionamide;CIS-N-(2-Cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-2-yl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-2-yl)-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-propionamide;CIS-3-[-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide;CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide;CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide;CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-propionamide;CIS-2-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-2-methyl-propionamide;CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-propionamide;CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[3-oxo-3-(3-oxo-piperazin-1-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-(2R)-1-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoyl]-pyrrolidine-2-carboxylicacid amide;CIS-N-(Carbamoyl-methyl)-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide;CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide;CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[8-(Ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[8-(Ethyl-methyl-amino)-1-methyl-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-2,2-Dimethyl-3-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-propionamide;CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide;CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide;CIS-3-[1-(Cyclobutyl-methyl)-8-ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-3-[8-(Ethyl-methyl-amino)-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-8-Dimethylamino-3-(2,2-dimethyl-3-morpholin-4-yl-3-oxo-propyl)-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamide;CIS-3-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-8-Dimethylamino-3-[3-(1,1-dioxo-[1,4]thiazinan-4-yl)-2,2-dimethyl-3-oxo-propyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;TRANS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamideTRANS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide;CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-propionamide;CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide;CIS-1-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)cyclopropanecarboxamide;CIS-3-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)oxetane-3-carboxamide;CIS-3-(1-(cyclopropylmethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide;CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanamide;CIS-3-(8-(dimethylamino)-1-((1-fluorocyclopropyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamideand the physiologically acceptable salts thereof.
 31. The compoundaccording to claim 1 for use in the treatment of pain.
 32. A medicamentcomprising a compound according to claim
 1. 33. A method of treatingpain in a subject in need thereof, said method comprising administeringto said subject an effective amount therefor of at least one compoundaccording to claim 1.